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Table of Contents

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NECTAR2017 Grand Hotel Malahide, Dublin

6th – 8th December 2017

Table of Contents

Wifi & Twitter .......................................................................................................................................... 1

Scientific Programme .............................................................................................................................. 2

Welcome Message .................................................................................................................................. 4

Sponsors .................................................................................................................................................. 5

Tom Isaacs ............................................................................................................................................... 6

HDdennomore ........................................................................................................................................ 7

Feats of Modest Valour ........................................................................................................................... 8

Speakers’ Directory ............................................................................................................................... 10

Datablitz Presentations ......................................................................................................................... 32

Datablitz Abstracts ................................................................................................................................ 34

Delegate List .......................................................................................................................................... 58

Notes ..................................................................................................................................................... 61

Wifi & Twitter WIFI: Follow instructions from hotel for access to Grand Hotel Wi-Fi.

NECTAR Twitter Handle: @NECTAR_EU Conference Hashtag: #NECTAR2017 Other relevant handles you may wish to tag: Neuroscience Ireland: @NeuroscienceIRL Science Foundation Ireland: @scienceirel Cure Parkinson’s Trust: @CureParkinsonsT FENS: @FENSorg BNA: @BritishNeuro

Scientific Programme

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Welcome Message

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Welcome Message

Dear friends and colleagues,

Céad míle fáilte romhaibh go léir chuig NECTAR 2017! It is with great pleasure that we welcome you

back to Ireland for just the 2nd time in the 27 year history of NECTAR gatherings. Dublin is our country’s

capital and we hope that you get some time to explore it while you are in Ireland.

This year we welcome a stellar line-up of speakers from all over the world – from Australia, Belgium,

Canada, Denmark, France, Ireland, Switzerland, the UK and the US. Thank you all so much for making

the trip to Dublin to share your latest research findings with us. We will start the conference on

Wednesday with a session largely focussing on the latest understanding of the genetic, molecular and

biochemical pathogenesis of Alzheimer’s disease, Parkinson’s disease and Huntington’s disease. This

will be followed on Thursday by two sessions focussing on the latest developments in cell and gene

therapies for neurodegenerative and demyelinating diseases. Finally, we will finish NECTAR 2017 on

Friday with a session centred on clinical updates and perspectives.

As always at NECTAR meetings, we will also have significant input into the scientific programme from

young researchers through the data-blitz presentations. In total, we will have 24 speakers who will

present on a diverse range of topics. Please take the opportunity to find the data-blitz speakers on the

breaks to find out more on their research.

The global Parkinson’s and neurodegenerative disease community suffered a great loss this year with

the unexpected and untimely death of Tom Isaacs on 31st May at just 49 years of age. Tom was

diagnosed with Parkinson’s at the young age of 27. Following a major fundraising and awareness

campaign, he co-founded the Cure Parkinson’s Trust which is dedicated to finding a cure for the

condition. Tom was an incredible inspiration to so many people and a great friend to NECTAR – he will

be terribly missed. To honour Tom’s commitment to finding a cure for Parkinson’s disease, the final

day of NECTAR 2017 will be dedicated to his memory, and we are delighted that his Cure PD colleague

Richard Wyse and his wife Lyndsey are able to join us for this event.

Also just to note that the dates for the next NECTAR meeting have already been set. NECTAR 2018 will

be held in Paris on Thursday 6th and Friday 7th December 2018. Our sincere gratitude to Philippe

Hantraye, Emmanuel Brouillet, Nadia Van Camp and Malin Parmar for hosting!

Finally … if you’re a social mediaphile, don’t forget to tweet any comments, observations or photos

you may have throughout this year’s conference: @NECTAR_EU, #NECTAR2017.

Dr Eilís Dowd

President of NECTAR

Sponsors

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Sponsors

The NECTAR2017 Organising Committee would like to thank the following organisations and

companies for their generous sponsorship of the conference.

Science Foundation Ireland http://www.sfi.ie/

Campaign for Alzheimer’s Research (Europe) https://www.alzheimers-care.info/

Cure Parkinson’s Trust https://www.cureparkinsons.org.uk/

Neuroscience Ireland https://neuroscienceireland.com/

Fáilte Ireland http://www.failteireland.ie/

Neuronal Signaling http://www.neuronalsignaling.org/

http://www.sfi.ie/

https://www.alzheimers-care.info/

https://www.cureparkinsons.org.uk/

https://neuroscienceireland.com/

http://www.failteireland.ie/

http://www.neuronalsignaling.org/

Tom Isaacs

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Tom Isaacs Tom Isaacs, co-founder of the Cure Parkinson’s Trust, was born on April 2, 1968. He died unexpectedly on May 31, 2017, aged just 49.

Tom qualified as a chartered surveyor and was working as a director of a London property company when he was diagnosed with Parkinson’s (PD) in 1995 - he was just 26. At that time, scientists and doctors accepted without question that Parkinson’s was an incurable condition and drugs were prescribed to alleviate symptoms of the disease. Progress in research was slow and pre-clinical work was focused on cause and needed to be more coordinated. Tom simply could not accept this and began asking “why?” and investigating the underlying state of affairs in the Parkinson’s community and research arena. He determined that one day he would be able to insert the words “used to” when he said ~ “I have Parkinson’s”. Sadly, that was not to be; but his incredible work in the intervening years between diagnosis and his death has brought this vision tantalisingly close for the many others with the condition.

Read more about Tom here:

Tom’s obituary in The Times: https://www.thetimes.co.uk/article/tom-isaacs-rsj52b76z

The Cure Parkinson’s Trust’s tribute to Tom https://www.cureparkinsons.org.uk/news/cpt-pd-community-mourns-the-loss

Donate in memory of Tom here:

https://www.cureparkinsons.org.uk/donate/inmemorytom/20/credit-card

https://www.thetimes.co.uk/article/tom-isaacs-rsj52b76z

https://www.cureparkinsons.org.uk/news/cpt-pd-community-mourns-the-loss

https://www.cureparkinsons.org.uk/news/cpt-pd-community-mourns-the-loss

HHdennomore

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HDdennomore HDdennomore (pronounced ‘Hidden No More’) is a global coalition of patient advocates dedicated to raising awareness of Huntington’s disease and ending the stigma and shame around the disease. On May 18, at Aula Paolo VI in Vatican City, Rome, Pope Francis became the first world leader to recognize the devastating plight of those living with and affected by Huntington’s disease.

Tom Isaacs was in many ways the inspiration for the HDdennomore movement. Amanda Spencer (Irish filmmaker and Huntington’s disease advocate) said “… the genesis of the idea for HDdennomore actually came through Tom Isaacs meeting the Pope in Rome. After that both Charles [Sabine] and Elena [Cattaneo] thought why not try for Huntington’s disease. His moment with the Pope inspired this whole movement in many ways.”

One of the lead organisers of the, Prof Elena Cattaneo, greets Huntington’s disease patient, Yosbely Soto Soto from Lake Maracaibo, Venezuela where the gene that causes HD was discovered in 1993. Read more here: http://hddennomore.com/

http://hddennomore.com/

Feats of Modest Valour

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Feats of Modest Valour Feats of Modest Valour was inspired by Tom Isaacs’ presentation at NECTAR 2014 in Galway. After the conference, excerpts from Tom’s presentation were shown to a roomful of filmmakers, and this film - a blend of science and medicine, scientists and patients, art and music - is the result. In Feats of Modest Valour, three individuals live clockwork existences, dictated by a strict regime of medication to manage the physical reality of living with Parkinson’s disease. Brian Carney is a farmer from County Mayo whose son had to take over the running of the family farm from a very young age; Milena Lulic is a Croatian World War II survivor who faces her condition head-on with great dignity; and Tom Hickey, the Irish actor, talks about how suffering for his art takes on a whole new meaning with the disease. Interwoven with their stories, we see researchers at NUI Galway’s Centre for Research in Medical Devices (CURÁM), led by NECTAR and Neuroscience Ireland President, Dr Eilís Dowd, who are developing a novel therapeutic approach which they hope will revolutionise treatment of the condition. Guided by stunning animated sequences, we delve into the brain of someone with Parkinson’s disease, and see how dying cells can be replaced by dopamine neurons supported by a natural biomaterial “scaffold”.

On Friday 20th October 2017, after eight days of science films from all over the world, Feats of Modest Valour, won the prestigious Scientist Award at the Imagine Science Film Festival in New York, and was also awarded the Runner-Up People’s Choice Award. The Scientist Award is awarded by the leading international science journal, Science, and its publisher, the American Association for the Advancement of Science (AAAS), to a film that portrays in an accurate and inventive way the life of a scientist. The select jury included Nobel prize-winning scientist, Professor Martin Chalfe, and award-winning science columnist for the New York Times, Professor Carl Zimmer.

The film is co-directed and co-produced by Mia Mullarkey and Alice McDowell of Ishka Films, and was

screened on Ireland’s premier television channel, RTÉ One, on Sunday November 12th 2017. Feats of

Modest Valour will be screened at the conference dinner at NECTAR 2017.

Feats of Modest Valour was produced through the ‘Science on Screen’ initiative between NUI Galway’s CÚRAM Centre for Research in Medical Devices, Science Foundation Ireland, and the Galway Film Centre who manage Galway’s UNESCO City of Film designation. Science on Screen was conceptualised as part of CURÁM’s Public Engagement Programme, and aims to facilitate, promote and increase the inclusion of science, technology, engineering and maths (STEM) content in Irish film and TV production. To find out more about the film, see www.featsofmodestvalour.com

http://www.featsofmodestvalour.com/

Feats of Modest Valour

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Robin Morgan is an American poet, author, political theorist and activist, journalist, lecturer, and

former child actor. In 2013, Morgan announced publicly that she had been diagnosed with Parkinson's

disease. The poem “No Signs of Struggle” is an account of her experience of the disease, and is where

the title for “Feats of Modest Valour” originated.

“No signs of struggle” by Robin Morgan

Growing small requires enormity of will: just sitting still in the doctor’s waiting room watching the future shuffle in and out, watching it stoop; stare at you while you try not to look.

Rare is an exchange: a smile of brief, wry recognition.

You are the new kid on the block. Everyone here was you once. You are still learning that growing small requires a largeness of spirit you can’t fit into yet; acceptance of irritating help from those who

love you; giving way and over, but not up.

You’ve swallowed hard the contents of the “Drink Me” bottle, and felt yourself shrink. Now, familiar furniture looms, floors tilt, and doorknobs yield only when wrestled round with both hands.

It demands colossal patience, all this growing small: your diminished sleep at night, your handwriting, your voice, your height.

You are more the incredible shrinking woman than the Buddhist mystic, serene, making do with

less. Less is not always more. Yet in this emptying space, space glimmers, becoming visible. Here is a place behind the eyes of those accustomed by what some would call diminishment.

It is a place of merciless poetry, a gift of presence previously ignored, drowned in the daily

clutter. Here every gesture needs intention, is alive with consciousness. Nothing is automatic. You can spot it in the provocation of a button, an arm poking at a sleeve, a balancing act at a night-

time curb while negotiating the dark. Feats of such modest valor, who would suspect them to be exercises in an intimate, fierce discipline, a metaphysics of being relentlessly aware.

Such understated power here, in these tottering dancers who exert stupendous effort on tasks most

view as insignificant. Such quiet beauty here, in these, my soft-voiced, stiff-limbed people; such resolve masked by each placid face.

There is immensity required in growing small, so bent on such unbending grace.

https://en.wikipedia.org/wiki/File:RobinMorgan_profile.jpg

Speakers’ Directory

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PROF LESLEY JONES Cardiff University, Wales

Biosketch: My main research interests are in neurodegenerative diseases, most particularly in Huntington’s disease (HD). HD is a rare inherited neurodegeneration caused by an expanded repeat section in the huntingtin gene on the short arm of chromosome 4. As part of a large collaborative effort, we identified the first genetic modifiers in HD in 2015 (GeM-HD http://dx.doi.org/10.1016/j.cell.2015.07.003). Our motivation in this study was to identify variation that could delay or precipitate disease onset as pathways that this variation lies in are ideal therapeutic targets, as we know they have this effect in people carrying the mutation. We are extending this study in collaboration with Jim Gusella, Marcy MacDonald and Jong-Min Lee (MGH, Boston USA). I am also the Lead

Facilitator of the Genetic Modifiers Working Group (GMWG) of the European Huntington’s Disease Network. I collaborate closely with SarahTabrizi (Institute of Neurology, UCL) and Peter Holmans, in Cardiff to integrate genetic and gene expression data from HD subjects to explore underlying pathology important in disease (10.1093/hmg/ddw142). In collaboration with Sarah Tabrizi and Henry Houlden we also showed that the signal we saw modifying onset in HD modifies onset in a series of spinocerebellar ataxias also caused by repeat expansion mutations (10.1002/ana.24656). A further collaboration with Sarah Tabrizi recently demonstrated that genetic variation in MSH3 contributes to modifying progression in HD. MSH3 is a mismatch repair gene, part of a system for detecting and correcting small DNA lesions. We know that crossing HD mice with those with Msh3 knocked out prevents somatic expansion of the HTT CAG repeat, thus implicating somatic expansion as the mechanism underlying the modification of HD age at onset and progression through the operation of the DNA damage response. I also work on Alzheimer’s disease (AD) where I have been particularly interested in pathway analyses of genetic and genomic data which have revealed new evidence implicating the immune response in AD susceptibility. Title: A genetic perspective on Huntington's disease pathogenesis Abstract: Huntington’s disease (HD) is an autosomal dominant neurodegeneration caused by an extended CAG repeat tract in the huntingtin gene (HTT). There are currently no disease-modifying treatments. We have known since 1993 that the polymorphic CAG repeat tract causes HD once it reaches 40 CAG repeats, and that the main contributor to differences in age at onset is the length of the CAG expansion. Expressing the expanded CAG repeat in cells and animals causes widespread molecular, cellular and behavioural phenotypes and deciding which of those are important to target in order to treat HD has been difficult. Part of the residual variation in onset, after the CAG length is taken into account, is heritable and therefore due to other genetic variation. We have used genetics to uncover which molecular pathways might contribute to the age at onset and progression of human HD and thus form the most appropriate therapeutic targets. The availability of large observational cohorts in HD, collected in preparation for clinical trials such as Registry and Enroll, have enabled the search for genetic modifiers of disease onset and other phenotypes. We have conducted genome-wide association studies that reveal genetic variation in the DNA damage response pathways as major contributors to disease onset and progression. In order to investigate whether this effect occurred at the level of the CAG repeat expansion in DNA we examined a number of other diseases caused by the same repeat mechanism that revealed a similar genetic signal in DNA damage response. We therefore think that this indicates that modification by this pathway occurs across these diseases through effects on the CAG repeat itself rather than at the huntingtin protein level. One possible mechanism underlying this is the somatic expansion of the repeat in germline and somatic dividing and non-dividing cells, to give longer repeats in individual cells that are intrinsically more damaging to those cells and cause more rapid cell death leading to neurodegeneration. Targeting members of the DNA damage response network implicated by our genetic studies is therefore a plausible avenue for therapeutic interventions in HD.

http://dx.doi.org/10.1016/j.cell.2015.07.003


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PROF MARIA SPILLANTINI University of Cambridge, England

Biosketch: Maria Grazia Spillantini is Professor of Molecular Neurology in the Clinical School of the University of Cambridge. She was born in Arezzo, Italy. After receiving a Laurea in Biological Sciences, summa cum Laude, in 1981 from the University of Florence, she pursued research at the Department of Clinical Pharmacology of the University of Florence, at the Unité de Neurobiologie of the INSERM in Paris and at the Molecular Neurobiology Unit of the Medical Research Council in Cambridge. In 1987 she moved to the Medical Research Council Laboratory of Molecular Biology, where first, working in Dr Michel Goedert’s group, she obtained a Ph.D. in Molecular Biology from Cambridge University and later worked as a postdoctoral fellow with

Prof. Sir Aaron Klug. In 1996 she moved to the Cambridge Centre for Brain Repair and in 2014 to the Clifford Allbutt Building both in the Department of Clinical Neurosciences of the University of Cambridge. Her group works on the molecular neuropathology of diseases characterised by tau and alpha-synuclein aggregates. With her collaborators, she identified alpha-synuclein as the main component of the filaments that form the Lewy bodies in Parkinson’s disease and dementia with Lewy bodies and described one of the first mutations in the MAPT gene leading to frontotemporal dementia and Parkinsonism linked to chromosome 17. She has received several international Prizes including the Potamkin Prize of the American Academy of Neurology and the Cotzias Prize of the Spanish Neurological Society. She was elected Fellow of the Academy of Medical Sciences, London in 2010 and Fellow of the Royal Society, London in 2013. She is Professorial Fellow at Clare Hall and a life member of Peterhouse, Cambridge.


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PROF VEERLE BAEKELANDT University of Leuven, Belgium

Biosketch: Veerle Baekelandt obtained a PhD in neurobiology at the KU Leuven, Belgium. She is currently professor at the department of neurosciences, faculty of medicine of KU Leuven and head of the Laboratory for Neurobiology and Gene Therapy. Over the last 15 years, Parkinson research has been fueled by the identification of genes that are linked to familial forms of the disease. The general approach of the lab consists of generating novel cellular and rodent models based on mutations involved in familial forms of PD, with the aim to better reproduce the pathogenesis of the disease than the existing models. Better disease models and insights in the molecular pathogenesis are required to develop novel causal therapeutic strategies that can cure or slow down the disease. Understanding the function of these genes will

undoubtedly also provide crucial insights into the pathogenesis of more common sporadic forms of PD. The current research focuses on the role of α-synuclein aggregation in PD and related synucleinopathies, and on the function of LRRK2, a kinase linked to PD. The lab is using viral vector technology, stereotactic neurosurgery and non-invasive molecular imaging as core technologies. The underlying hope is that the generation of more relevant models in cells and in rodent brain will lead to a better insight into the molecular pathogenesis of PD and to the development of new therapeutic strategies and drugs. Title: Modeling alpha-synuclein aggregation, propagation and neurotoxicity in rodent brain Abstract: Misfolded protein aggregates are a common feature of several neurodegenerative diseases. The recent discovery of the transmissible nature of amyloidogenic proteins suggests a hypothesis of a pathogenic trigger which might spread throughout the nervous system underlying the progression of the disease. There is emerging evidence that these protein aggregates can adopt distinct conformations or ‘strains’ characterized by noticeable differences in phenotypic traits. α-Synuclein aggregation is considered to play a central role in multiple neurodegenerative diseases, such as Parkinson’s disease (PD), Multiple System Atrophy (MSA) and Dementia with Lewy Bodies (DLB). This has led to the hypothesis that strains might account for the distinct clinico-pathological traits within synucleinopathies. We assessed the properties of structurally well-defined alpha-synuclein assemblies (oligomers, ribbons and fibrils) after injection in rat brain. We proved that alpha-synuclein strains amplify in vivo. Fibrils seemed to be the major toxic strain, resulting in progressive motor impairment and cell death, whereas ribbons caused a distinct histopathological phenotype displaying Parkinson’s disease and multiple system atrophy traits. Additionally, we showed that alpha-synuclein assemblies cross the blood–brain barrier and distribute to the central nervous system after intravenous injection. Our results demonstrate that distinct alpha-synuclein strains display differential seeding capacities, inducing strain-specific pathology and neurotoxic phenotypes. We are currently further exploring whether these distinctive neurotoxic and pathological prion-like effects of alpha-synuclein strains might provide a basis for the heterogeneity observed in synucleinopathies.


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PROF ROBERT LAHUE National University of Ireland Galway, Ireland

Biosketch: Bob Lahue earned an undergraduate degree in chemistry (Univ. of Virginia) and a PhD in biochemistry (Univ. California Berkeley). He trained as a postdoc in biochemistry at Duke Univ. in the lab of Paul Modrich, co-winner of the 2015 Nobel Prize in Chemistry. From 1989-2007, Bob held faculty positions at the Univ. Massachusetts Medical Centre and the Univ. Nebraska Medical Centre, where his research was supported by NIH, the American Cancer Society and the Huntington’s Disease Society of America. In 2007, Bob moved to the National University of Ireland Galway where his work has been supported by Science Foundation Ireland, the Irish Health Research Board and the European Huntington’s Disease Network. In 2014, Bob began a fruitful collaboration with Dr Silvia Ginés of

the University of Barcelona. Using an HDAC3-selective inhibitor kindly provided by BioMarin Pharmaceuticals, the Lahue and Ginés labs investigated the potential therapeutic effects of the HDAC3-selective inhibitor in HD mice. The results of that study will be presented in Bob’s presentation to NECTAR 2017. Title: Slowing a runaway train: targeting histone deacetylase 3 in Huntington’s disease Abstract: Huntington’s disease (HD) is a neurodegenerative disorder whose major symptoms include progressive motor and cognitive dysfunction. Cognitive decline is a critical quality of life concern for HD patients and families. The enzyme histone deacetylase 3 (HDAC3) appears to be important in HD pathology by negatively regulating genes involved in cognitive functions. Furthermore, HDAC3 has been implicated in the aberrant transcriptional patterns that help cause disease symptoms in HD mice. HDAC3 also helps fuel CAG repeat expansions in human cells, suggesting that HDAC3 may power striatal expansions in the HTT gene thought to drive disease progression. This multifaceted role suggests that early HDAC3 inhibition offers an attractive mechanism to prevent HD cognitive decline and to suppress striatal expansions. This hypothesis was investigated by treating HdhQ111 knock-in mice with the HDAC3-selective inhibitor RGFP966. Chronic early treatment prevented long-term memory impairments and normalized specific memory-related gene expression in hippocampus. Additionally, RGFP966 prevented corticostriatal-dependent motor learning deficits, significantly suppressed striatal CAG repeat expansions, partially rescued expression of striatal protein markers and reduced accumulation of mutant huntingtin oligomeric forms. These novel results highlight RGFP966 as an appealing multiple-benefit therapy in HD that concurrently prevents cognitive decline and suppresses striatal CAG repeat expansions.


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PROF MARINA LYNCH Trinity College Dublin, Ireland

Biosketch: My research focuses on investigating the contribution of neuroinflammatory changes in the age-related and amyloid β-induced deterioration in synaptic function in the brain, especially in the hippocampus. A key component of neuroinflammation is activation of microglia and astrocytes and therefore a particular objective is to understand the factors which trigger activation of these cells, with the aim of modulating these changes and restoring synaptic function. Current work includes an evaluation of the role of cell-cell interaction in modulating microglial activation with a special focus on assessing the interaction between

CD200 and its receptor. Among the factors which upregulates CD200 expression is the anti-inflammatory cytokine, IL-4 and recent studies have provided evidence that some novel anti-inflammatory agents attenuate age- and amyloid β-induced changes in hippocampus because they exert an effect on IL-4 and CD200 expression. My current research group consists of 6 postdoctoral fellows and 9 PhD students.


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PROF GIOVANNA MALLUCCI University of Cambridge, England

Biosketch: Giovanna Mallucci is a Professor in the Department of Clinical Neurosciences at the University of Cambridge. She is a specialist in neurodegenerative diseases and the programme leader in the MRC Toxicology Unit. Professor Mallucci studied Medicine at Oxford and University College London, then specialized in neurology. She gained her PhD in 2001 from Imperial College, London, for her work on transgenic models of prion disease, after which she combined scientific and clinical careers. In 2008, she joined the MRC Toxicology Unit as Programme Leader, focusing on generic mechanisms of neurodegeneration. She is Honorary Consultant Neurologist at Addenbrooke's Hospital, with a specialist interest in dementia.

Professor Mallucci has the job of leading the new centre on Cambridge Biomedical Campus] tasked with finding new ways to diagnose, treat, prevent and care for people with dementia. The centre joins others at Cardiff University, the University of Edinburgh, Imperial College London and King’s College London in forming the new UK Dementia Research Institute (UK DRI).


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DR CLARE PARISH Florey Institute of Neuroscience & Mental Health, Melbourne, Australia

Biosketch: Associate Professor Clare Parish heads the Stem Cells and Neural Development laboratory at the Florey Institute of Neuroscience & Mental Health in Melbourne, Australia. She obtained her PhD from Monash University, Australia in 2002 and subsequently spent 5 years at the Karolinska Institute (Stockholm, Sweden) under the mentorship of Professor Ernest Arenas. She returned to Australia in 2007 to establish her own research group. She has 68 peer-reviewed publications spanning her major research interests in stem cells and development, neural

transplantation and neural engineering. Clare has a broad research interest relating to repairing the injured brain. Her research team places a strong emphasis on understanding neural development, with the idea that repairing the injured brain will require recapitulation of many of these early events. Consequently there are a number of major research themes running within the laboratory, including: understanding the neural development; directed differentiation of human pluripotent stem cells; molecular mechanisms underlying axonal targeting and synaptogenesis and improving cell-replacement therapy for neural injuries. While the past 15 years has had a strong focus on understanding dopamine development and developing cell replacement therapies for Parkinson’s disease, more recently the team has expanded its interests to apply similar approaches for other neural injuries including. Her research has now also adopted a major focus on the utility of bioengineered scaffolds for neural applications – assessing the potential of biomaterials to provide structural and functional support for neurons in vitro and during transplantation. Title: Tracking and promoting plasticity of hESC-derived dopaminergic neurons in the Parkinsonian brain Abstract: The development of effective stem cell-based therapies for Parkinson’s disease will require the generation of clinically relevant replacement dopamine neurons. Prior to advancing to the clinic it will be important to have an in-depth understanding of the integration of these cells in vivo. Using novel LMX1A- and PITX3-eGFP human embryonic stem cell lines we have developed and assessed an animal product-free ventral midbrain differentiation protocol amenable to clinical translation. Analysis of grafted PITX3-eGFP dopaminergic cells revealed that the major A9 and A10 subclasses innervate host brain with subtype-specificity. However, the majority of graft-derived innervation remains non-dopaminergic. In order to increase the dopamine component and innervation of host tissue, we combined FACS purification for DA progenitors with neurotrophic support by the overexpression of GDNF within striatal target tissue. Combinatorial cell transplantation and GDNF overexpression improved fine motor recovery compared to cell transplantation or GDNF alone. GDNF increased A9/A10 specification of progenitors and modulated dopaminergic innervation. Crucially these results underline the promise of stem cell-based therapies for Parkinson’s disease as well as emphasize the scope for further refinement of differentiation and transplantation protocols.


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DR TILO KUNATH University of Edinburgh, Scotland

Biosketch: Tilo Kunath carried out his PhD at the Samuel Lunenfeld Research Institute at the University of Toronto. His postdoctoral studies at the Institute for Stem Cell Research in Edinburgh were focused on neural induction and differentiation of mouse and human embryonic stem cells. He has run his own laboratory at the University of Edinburgh since 2007 initially as a Parkinson’s UK Senior Research Fellow. He has pioneered the use of patient-specific iPS cell technologies to establish models of Parkinson’s disease.

Currently, he is funded to drive forward the use of human ES cells for use in cell replacement therapies for Parkinson’s disease and for disease modelling with familial Parkinson’s iPS cell lines. He has also ventured into rat models of Parkinson’s to complement the cell models. His lab is focussed in two main areas (i) understanding how the protein, alpha-synuclein, causes degeneration of neurons in Parkinson’s, and (ii) producing a cell-based therapy for Parkinson’s. Central to this aim is generation of midbrain dopaminergic neurons from human pluripotent stem cells. We use patient-derived material to generate induced pluripotent stem cells (iPSCs) with genetic mutations known to cause Parkinson’s.


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DR MARINA ROMERO-RAMOS Aarhus University, Denmark

Biosketch: Dr. Romero-Ramos graduated from the University of Sevilla where she received her PhD degree “suma cum laude” in 2000 at the Department of Biochemistry and Molecular Biology. Her thesis work focused on the role of antioxidants in the dopaminergic system. Later she moved to USA to start her postdoctoral training with Prof. M-F Chesselet at UCLA School of Medicine, studying the use of non-neural stem cells for neural replacement. In the summer 2002, she became a Marie Curie Fellow and during the following 3 years worked characterizing viral vector based alpha-synuclein model of Parkinson’s Disease with Prof. D. Kirik and Prof. A. Bjorklund in Lund University (Sweden). She is now Associate Professor at the Health Faculty,

Aarhus University (Denmark), where she leads the CNS Disease Modeling group since 2006. Her lab is affiliated to the EMBL node on translational Neuroscience, DANDRITE. Her research interest is focused on the study in animal models of the different factors involved in the neurodegeneration in Parkinson’s disease, such as protein mishandling and inflammatory events Title: CD163+ cells as modulators of the immune response related to Parkinson’s’ Disease Abstract: Neuroinflammation has been long proposed to be associated to Parkinson’s’ disease (PD). Findings in patients and also in animal models of the disease suggest that not only microglia in brain, but also peripheral immune cells, such monocytes/macrophages and lymphocytes play a role in the immune response in PD. This immune response seems dynamic and might have a significant role in the neuronal fate. Our data suggest that among the immune cells, those expressing the membrane receptor CD163 are especially relevant. CD163 is a scavenger receptor exclusively express in the membrane of monocytes and macrophages but, not in microglia. We found that the CD163+ population infiltrates the brain during dopaminergic degeneration. The modification of this population using targeted drugs or a targeted depletion of the CD163+ cells resulted in decreased dopaminergic cell death in a toxic model of PD. The possibility of designing, targeted strategies to change the CD163+ population seems to be a promising tool to achieve neuroprotection using peripherally administered drugs. We will present in the talk, data in rodents and human supporting a significant role for this receptor in the disease, and its therapeutic potential.


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PROF HAROLD ROBERTSON Dalhousie University, Canada

Biosketch: Harold Robertson, Ph.D., F.R.S.C. is Professor Emeritus in the Department of Pharmacology, Faculty of Medicine, Dalhousie University. He is also Professor of Psychiatry at Dalhousie and adjunct Professor at the Atlantic Veterinary College, University of Prince Edward Island. He obtained his Ph.D. in Zoology at the University of Cambridge in England (1974) and did postdoctoral work in Saskatoon, Oxford (UK) and the Max Planck Institute for Experimental Medicine, Göttingen, Germany. He joined Dalhousie University in 1978 as Assistant Professor of Pharmacology. In 1995, he was appointed Carnegie and Rockefeller Professor of Pharmacology and Head of the Department, a position he held for a decade. He has been visiting Professor at the University of

Cambridge, the Massachusetts Institute of Technology, the Karolinska Institute (Sweden) and was the first Neurofortis visiting Professor at Lund University (Sweden). His laboratory was the first to show that dopamine can increase gene expression in brain. They also discovered, cloned, sequenced and demonstrated increased expression of the gene synaptotagmin 10, now recognized as important in insulin’s effects in the brain. With Ben Rusak, he showed that light increases c-fos expression in the suprachiasmatic nucleus. Dr. Robertson was part of the Neural Transplantation Program at Dalhousie University from its beginnings in the mid-1980’s. In total 15 Parkinson’s sufferers were treated. With Ivar Mendez, Dr. Robertson was a founder of the Halifax Brain Repair Centre. He was elected President of the Canadian College of Neuropsychopharmacology (2008-2010). He left Dal in 2008 and has worked with a biotech company, Neurodyn Inc, to develop new treatments for Parkinson’s disease. Together with Dr. Jackalina Van Kampen he showed that ginseng might have potential as a treatment for Parkinson’s disease. They also showed that neurogenesis in substantia nigra can be increased by D3 dopamine receptor agonists. Currently Dr. Robertson is also lead investigator for a clinical project studying the relationship between loss of sense of smell and microstructural changes in olfactory bulb and tract in premotor Parkinson’s disease. In 2010, Dr. Robertson was elected to the Royal Society of Canada. Title: Finally, a new progressive rat (yes, rat!) model for Parkinson's disease Abstract: A number of recent reviews have drawn attention to the fact that the lack of good animal models for PD is now hampering progress towards an effective treatment (1). We have developed an animal (rat) model based on the toxic factor (β-sitosterol β-D-glucoside) found in the cycad nuts thought to be responsible for the ALS-Parkinson’s disease with dementia found on the island of Guam after WW2 (2). In this model, rats are fed for 16 weeks with β-sitosterol β-D-glucoside. Feeding is halted at 16 weeks and the phenotype develops slowly over the next 6 months. The first ef -synuclein accumulation in anterior olfactory structures and a loss of sense of smell. This is followed by loss of dopamine terminals in striatum and dopamine neurons in substantia nigra pars compacta. Finally, proteinase K-resistant intracellular α-synuclein aggregates appear in hippocampus and cortex, concomitant with changes in cognition (radial arm maze). This model is not yet perfect. We have no mechanism of action, no time course, no dose –response curve. Nevertheless, this model offers the potential to reproduce the changes in pre-motor PD as well as the cognitive effects seen in PD with dementia. The slow, progressive development of pathological changes is an inconvenience but PD development we know occurs over years and possibly even decades. It is therefore to be expected that a good model would develop slowly. References: 1. Beal, M.F. (2010). Parkinson's disease: a model dilemma. Nature 466, S8-10. 2. Van Kampen JM, Baranowski DC, Robertson HA, Shaw CA, Kay DG.(2015) The Progressive BSSG Rat Model of Parkinson's: Recapitulating Multiple Key Features of the Human Disease. PLoS One. 2015 Oct 6;10(10):e0139694. doi: 10.1371/journal.pone.0139694. eCollection 2015.


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DR CLAIRE RICE University of Bristol, England

Biosketch: Dr Claire Rice is a Consultant Senior Lecturer in Multiple Sclerosis Neurology at the Institute of Clinical Neurosciences in Bristol. She was awarded a BA (Hons) in Neuroscience from Cambridge University in 1996 and completed her undergraduate medical training in Cambridge, qualifying in 1998. Dr Rice's post-graduate neurology training was based at Frenchay Hospital in Bristol although she also worked at the National Hospital for Neurology and Neurosurgery, Queen Square, London and at Royal United Hospital in Bath. Her doctoral research focused on the development of bone marrow-derived cell therapy for multiple

sclerosis (MS) and she was awarded a PhD from Bristol University in 2008. Dr Rice works with the MS team at the Bristol and Avon MS Unit (BrAMS), Southmead Hospital and runs a specialist clinic in Neuroinflammatory disease as well as participating in the general neurology service at Southmead Hospital. The aim of her on-going laboratory-based research is to improve repair in MS and she has been actively involved, together with Professor Scolding in Bristol, in setting up clinical trials of bone marrow-derived cell therapy in progressive MS. Title: Cell therapy for the treatment of progressive multiple sclerosis Abstract: Multiple sclerosis (MS) is a chronic neurological disease that affects more than 2 million people worldwide. In recent years, significant progress has been made in the development of a variety of treatment options for relapsing-remitting MS. However, these are predominantly immunomodulatory therapies; none directly promotes repair and relatively little effect on the accumulation of disability that characterises progressive MS has been demonstrated. As our understanding of the pathophysiology of progressive MS evolves, there is a growing awareness that although immunotherapy is important, a broader therapeutic approach including neuroprotection and CNS repair is likely to be required if we are to treat progressive MS effectively. Target mechanisms for potential therapies include reduction of oxidative stress, restoration of mitochondrial function, promoting remyelination and intervening to minimise negative consequences of chronic demyelination, including trophic factor withdrawal and pathological changes in axonal ion channel expression. For MS and other complex human diseases, the potential of cell therapy to harness the multiplicity of reparative properties of endogenous cell populations has been appreciated. In particular, bone marrow-derived cells including multipotent mesenchymal stromal cells (MSC) have been the subject of intense interest given their relative accessibility, ease of culture in vitro and the increasing appreciation of their potential therapeutic properties including immunomodulation and neuroprotection. A variety of approaches are in development and each has potential advantages as well as safety concerns. These will be discussed together with an update on relevant, ongoing clinical trials.


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PROF NICHOLAS MAZARAKIS Imperial College London, England

Biosketch: Professor Nicholas D. Mazarakis holds the Lucas-Lee chair of Molecular BioMedicine and is head of Gene Therapy in Brain Sciences, Faculty of Medicine, Imperial College London. He is a molecular neuroscientist with an international reputation in gene therapy of neurological diseases. He has served as Vice President of Neurobiology at Oxford BioMedica, where he pioneered the first ever lentiviral gene therapy to the clinic for Parkinson’s disease (ProSavin®). His research focuses on investigating molecular pathways of neurodegeneration and developing translational gene therapies for neurological diseases. He received his Ph.D. from King’s College University of London and is an elected fellow of the Society of Biology. He has lectured in conferences worldwide and published in top science journals such as Nature, Science and PNAS. His research is supported by several grants including an Advanced

Investigators award in 2008 and a Proof of Concept grant in 2013 from the European Research Council.


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PROF LESLIE THOMPSON University of California, Irvine, US

Biosketch: Leslie M. Thompson, PhD, is a Professor at the University of California, Irvine (UCI) in the Departments of Psychiatry and Human Behavior and Neurobiology and Behavior and a member of UCI MIND, the Sue and Bill Gross Stem Cell Center and the Center for the Neurobiology of Learning and Memory. Dr. Thompson has studied Huntington’s disease, a devastating neurodegenerative disease, for most of her scientific career and was a member of the international consortium that identified the causative gene for HD in 1993. The Thompson laboratory now focuses on understanding mechanisms that underlie HD and Amyotrophic Lateral Sclerosis and how this understanding can assist in developing treatments for the disease, including using induced pluripotent stem cells to model disease symptoms in a dish and CIRM-funded preclinical studies

to use stem cell-based transplantation approaches for HD. The iPSC research ranges from approaches to reduce accumulation of the mutant protein to genomic and bioinformatics analysis of patient-derived neural cells. Dr. Thompson received her bachelors of arts degree from UC San Diego and her PhD from UCI. She continued at UCI for her postdoctoral work in the laboratory of John Wasmuth, where she began her collaborative studies on HD. She joined the faculty as an Assistant Professor at UCI in 2000. Dr. Thompson is an AAAS Fellow, a member of the Hereditary Disease Foundation HD Cure Committee, Huntington Study Group Scientific Affairs Committee, and is founding Co-Editor in Chief of the Journal of Huntington’s Disease. She is a principal investigator on the Answer ALS program, multiple grants from the National Institutes of Health, including a recent multi-institution LINCS Center grant from NIH to define cell signatures for neurodegenerative disease, and on stem cell grants funded by the California Institute for Regenerative Medicine. Title: Neural stem cell transplantation for Huntington’s disease Abstract: Huntington’s disease (HD) is an inherited neurodegenerative disorder with no disease modifying treatment. Expansion of the glutamine-encoding repeat in the Huntingtin (HTT) gene causes broad effects that are a challenge for single treatment strategies. Strategies based on human stem cells offer a promising option. To evaluate the potential efficacy of hNSCs, we transplanted a GMP grade human embryonic stem cell (hESC) derived hNSC line into a HD fragment R6/2 mouse model. Implanted cells provided modification of behavioral phenotypes, survived and showed potential to differentiate into several neural cell types. hNSCs were electrophysiologically active, rescued some electrophysiological alterations in R6/2 mice, and were contacted by mouse host nerve termini. Transplantation also improved motor impairment and cognition in a full length Q140 HD mouse model. Mechanistically, the accumulation of a high molecular weight HTT species, which closely corresponds to pathogenesis (Ochaba et al., 2016), was substantially reduced by the hNSC treatment in R6/2 mice. Visible inclusions were also lowered in both models. Finally, improvement was associated with increased trophic support as brain-derived neurotrophic factor (BDNF) was increased with implantation.


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PROF ANNE-CATHERINE BACHOUD-LÉVI Mondor Biomedical Research Institute, Créteil, France

Biosketch: Our team is built at the interface between basic research in cognition and clinical research in brain therapies. We address two questions: 1) the bases of specifically human cognitive functions (language and social cognition), and the role of the striatum in such functions; 2) the relation between brain reconstruction and functional reconstruction (rehabilitation and grafting). Because Huntington's Disease is predominantly characterized by a neural degeneration targeting the striatum, we used it as a model both for striatal lesion and for cell therapy and neuroprotection. We combine large scale studies in cell therapy and basic research in

cognition. This specificity enables us for the first time to use intracerebral grafting as a model of plasticity in human beings and to integrate therapeutics in basic research in cognition. In addition, we develop cognitive programs in language and social cognition within the Département d’Etudes Cognitives (ENS) and transfer them to brain pathology.


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PROF NICOLE DÉGLON University of Lausanne, Switzerland

Biosketch: Prof. Déglon received her education, including a Ph.D. in Biochemistry, at the University of Lausanne, Switzerland. She held several research positions at the Gene Therapy Centre in Lausanne, at the Salk Institute in San Diego, California, and at the Federal Polytechnic Institute of Lausanne, Switzerland where she developed gene therapy approaches for neurodegenerative diseases. In 2003, she joined the French Atomic Energy Commission (CEA) as Research Director and Deputy Director of MIRCen, a pre-clinical imaging platform for drug, cell and gene therapy. She is currently associate Professor in the Department of Clinical Neurosciences (DNC) at the Lausanne University Hospital (CHUV). Prof. Déglon’s research interests include the development of viral-based genetic models of neurodegenerative

diseases and the treatment of neurodegenerative diseases from cell transplantation to gene therapy. In 1997, her group was one of the first to adopt the powerful gene transfer technology with lentiviral vectors for neurotrophic factor delivery to the brain. Papers in this new research line have opened entirely new possibilities for efficient, long-term delivery of therapeutic genes in rodent and primate models of neurodegenerative diseases. She has also played a pioneer role in the modelling of CNS neurodegeneration by overexpressing disease causing proteins with viral vectors. In 2002, she developed lentiviral-mediated RNA interference and since then we have acquired a large expertise in the design and applications of siRNA sequences to silence dominant, toxic genes implicated in neurological disorders (HD and SCA3). The recent development of gene editing with CRISPR/Cas9 system has opened new opportunities for the modelling and treatment of HD. Title: The self-inactivating Kamicas9 system for HTT gene editing Abstract: Genome editing with the CRISPR/Cas9 system is making possible to modify the sequence of genes linked to these diseases in the adult brain. Here, we developed the kamiCas9 self-inactivating CRISPR/Cas9 system. This system was designed for a transient expression of the Cas9 nuclease while preserving high editing efficiency. In the first application of this technology to neurodegenerative disorders, the gene responsible for Huntington’s disease (HD) was targeted in adult mouse neuronal and glial cells. Mutant huntingtin (HTT) was efficiently inactivated in mouse models of HD, leading to an improvement in key markers of the disease. Sequencing of potential off-targets with the constitutive Cas9 system in differentiated human iPS cells, revealed a very low incidence with only one site (OT1) above background level. Importantly, OT1 off-target frequency was drastically reduced with the kamicas9 system. These results demonstrate the potential of the self-inactivating CRISPR/Cas9 editing for applications in the context of neurodegenerative diseases.


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PROF SARAH TABRIZI University College London, England

Biosketch: Professor Sarah J Tabrizi BSc (Hons) MBChB (hons) FRCP PhD FMedSci graduated in Biochemistry, then studied medicine at Edinburgh University where she was awarded the 1992 Leslie Gold Medal for the most distinguished medical graduate. During her time as a trainee neurologist at the National Hospital for Neurology and Neurosurgery (NHNN), Queen Square, Sarah worked for Professors Anita Harding and David Marsden, both of whom would make a lasting impression on her. She undertook an MRC Clinical Training Fellowship PhD studying mitochondrial dysfunction in neurodegeneration

with Tony Schapira and Gill Bates from 1996-1999, and it was during this time that Sarah developed a passion for Huntington’s disease (HD) research. Sarah obtained a prestigious Department of Health National Clinician Scientist Fellowship at the UCL Institute of Neurology in 2002, was promoted to UCL Clinical Senior Lecturer and Honorary Consultant Neurologist in 2003, to Reader in 2007 and Full Professor in 2009. Sarah is Director of the UCL Huntington’s Disease Centre which she co-founded with Professor Gill Bates in 2016. Since 2003, she has led a highly effective and innovative clinical service for patients and families with Huntington’s disease at the NHNN. Sarah’s research programme seeks to discover effective disease-modifying treatments that prevent or reverse the neurodegenerative process in HD. She leads an internationally recognised research group which follows two distinct but complementary approaches; basic bench science focusing on cellular mechanisms of neurodegeneration, and a translational research programme in HD. Amongst her achievements, she has identified a key role for the innate immune system in the pathogenesis of HD, published the first assay of mutant HD protein in human blood cells, and led two major, international multidisciplinary research initiatives, TRACK-HD and Track-On HD. To date, the Track studies have yielded fundamental new insights into the preclinical phase of neurodegeneration in HD including identifying predictors of disease onset, progression, and neurobiological changes occurring twenty years before predicted disease onset, and her team developed new outcome measures now being used in four global phase 1/2 HD clinical trials. Sarah is currently clinical global PI for the world’s first HTT lowering (‘gene-silencing’) trial in HD, IONIS-HTTRx, sponsored by Ionis pharmaceuticals, which started in September 2015. She has published over 250 peer-reviewed publications to date, and her research work has been the subject of articles in NEJM, The Economist, Scientific American, and The Lancet. Sarah co-founded the UK All Party Parliamentary Group for HD in 2010, and was elected as a Fellow of the UK Academy of Medical Sciences in 2014 for outstanding contribution to medical research. Title: Meeting the therapeutic challenge in Huntington’s disease Abstract: Huntington’s disease (HD) is a devastating autosomal dominantly inherited neurodegenerative disease for which there is currently no effective disease modifying therapy. The genetic predictability of HD provides an opportunity for early therapeutic intervention many years before overt symptom onset and at a time when reversal or prevention of neural dysfunction may still be possible. As HD is monogenetic, fully penetrant, and characterised by a long premanifest phase, it is emerging as a potential model for studying therapeutic intervention in other neurodegenerative conditions such as Alzheimer’s or Parkinson’s disease where no preclinical diagnostic tests exist. Understanding of HD pathogenesis is evolving, and there are a number of candidate therapeutics with potential disease-modifying effects that are currently being tested. In my talk, I will update on new insights into HD pathogenesis and genetic modifiers of disease progression, our work to understand the neurobiology of the preclinical phase of neurodegeneration and neural compensation and plasticity in HD, and give an overview on exciting advances working towards HD gene silencing in humans.


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DR ALAN WHONE University of Bristol, England

Biosketch: Dr. Alan Whone is Senior Lecturer in Movement Disorders at the University of Bristol and Consultant Neurologist to Frenchay Hospital, Bristol. Prior to training in neurology in the South West, Alan undertook a PhD in Parkinson’s disease and other movement disorders at the Cyclotron Unit, Hammersmith Hospital , London, with Professor D J Brooks. Presently, Alan runs a regional movement disorders clinic at Frenchay where a significant part of his clinical role is to support the functional neurosurgery for movement disorders programme. His

current research programme includes clinical investigations of novel target regions for DBS in PD (the pedunculopontinenucleus) and growth factor infusions (GDNF) in PD, both of which he is investigating with Professor Stephen Gill. Alan also runs non surgical clinical investigations into cognitive and axial complications in PD and oversees preclinical (lab based) investigations into novel neuroprotective approaches, including assessing the potential utility of bone marrow stromal cells as a cell based therapy in Parkinson’s disease.


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PROF THOMAS FOLTYNIE University College London, England

Biosketch: Professor Tom Foltynie is Consultant Neurologist at

the Sobell Department of Motor Neuroscience at the UCL

Institute of Neurology and National Hospital for Neurology and

Neurosurgery, Queen Square, London. He completed

Neurology training in Cambridge where he undertook his PhD

in the Epidemiology & genetics of Parkinson’s disease. He is

responsible for Movement disorder patients, particularly PD

patients undergoing advanced treatments such as DBS,

Apomorphine and Duodopa. He is chief investigator for a trial

of Exenatide- a potential neurorestorative treatment for PD, as

well as the lead clinician at UCL for a multi-centre trial of fetal

dopaminergic cell transplantation for PD, and a proposed trial

of Deep Brain stimulation as a treatment for the cognitive

problems associated with advanced PD. Dr Foltynie is also leading a trial of Deep Brain Stimulation for

the treatment of patients with severe Tourette syndrome. Aside from trial involvement, PD patients

with and without DBS are being recruited to research looking at the influence of genetics on PD risk

and clinical progression, and the use of functional imaging to explore the mechanism of action of DBS

surgery.

Title: Exenatide as a treatment for Parkinson’s disease Abstract: Exenatide is a licensed treatment for type 2 Diabetes mellitus. It stimulates insulin release in the presence of elevated blood glucose, suppresses glucagon release and increase pancreatic beta islet cell mass. It has also been shown to have neurotrophic properties in vitro and protects against dopaminergic cell loss in the toxin based rodent models of Parkinson’s disease. Data will be presented to show that exenatide also has beneficial actions in alpha synuclein based models of PD. The majority of the talk will present data from 2 small randomized trials of exenatide in PD patients. The first of these was an open label trial, which reported an advantage of 1 year exenatide exposure in the motor severity of PD that persisted even a year after the drug was stopped. The second was a double blind trial which again detected an advantage of 1 year exenatide exposure in the motor severity of PD that persisted beyond the period of treatment exposure. These results will be critically appraised alongside a presentation of unpublished data documenting changes in markers of central insulin resistance in patients exposed to exenatide in the most recent trial.


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DR KYRIACOS MITROPHANOUS Oxford Biomedica, England

Biosketch: Dr Kyriacos Mitrophanous is Chief Scientific Officer at Oxford BioMedica Plc. Dr Mitrophanous joined Oxford BioMedica in 1997. He has over 20 years of lentiviral vector experience covering a range of technical disciplines, including the development of gene and cell therapies, delivery platform technologies, bioprocessing and analytics. He is a recognised world-class expert in the field, a named inventor on numerous lentiviral vector patents and an author of a number of key papers, which have been published in The Lancet and Human Gene Therapy. In his current role, he is responsible for the development of Oxford BioMedica’s new product candidates and LentiVector® platform. He holds a PhD in Molecular Biology from University College London and has conducted post-doctoral

research at the University of Oxford. He is a member of the UK BioIndustry Association Cell and Gene Therapy Advisory Committee. Title: Prosavin®, a dopamine gene therapy for advanced Parkinson’s disease: 5 years phase I/II clinical update Abstract: Parkinson’s disease (PD) is caused by the progressive degeneration of dopaminergic neurons. The primary standard of care for PD is oral dopaminergic based therapies; although these are initially highly efficacious, over time they lead to debilitating long term side effects that seriously impact on the quality of life thus restricting their long term effectiveness. As such, a therapy that provides a more continuous and local supply of dopamine to the site of pathology provides a potential approach for the development of new therapeutic strategies. ProSavin® is a gene therapy product that utilises a lentiviral vector to transfer three genes that are critical for de novo dopamine biosynthesis in the striatum, that is depleted of dopamine in PD. Fifteen advanced PD patients have received ProSavin® in three dose cohorts. ProSavin® has been demonstrated to be safe and well tolerated at all doses evaluated to date. No serious adverse events related to the study drug or surgical procedures were observed. All patients demonstrated improvement over baseline at both 6 and 12 months, which were sustained in most patients up to four years. To increase the efficacy further we have generated OXB-102, an improved version of ProSavin®, that expresses the same enzymes but with an increased DA production per genetically modified cell. Results from an efficacy study and a 6-month toxicology and biodistribution study indicate that the OXB-102 vector is efficacious, safe and well tolerated following stereotactic administration into the putamen and the vector does not significantly spread beyond the site of administration. A Phase I/II clinical trial of OXB-102 in the UK and France in PD patients is in planning. The project has been supported by the UK Technology Strategy Board (Innovate UK).


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DR SARAH-JANE RICHARDS Ormer Ltd., Wales

Biosketch: Dr. Sarah-Jane Richards trained in neuroanatomy, undertook post doc studies at Babraham Cambridge and St Mary’s Hospital London, and ran her own research group at the Department of Medicine, Addenbrookes Hospital, Cambridge studying the molecular biology of Alzheimer’s disease and Down’s syndrome. In the 1990s she founded the charities the Alzheimer’s Research Trust, now Alzheimer’s UK, and the Campaign for Alzheimer’s Research in Europe. In 2000 she retrained in law and now runs a successful medico-legal consultancy, Ormer Ltd, specialising in product liability relating to the safety and efficacy of medicinal devices and pharmaceutical products. She is HM Assistant Coroner for South Wales Central and is based in France.

Title: From Scientific Translation to Medical Regulation and Marketing Abstract: Medical research strives to provide innovative treatments to tackle illness, disease and debilitating conditions. The delivery of research outcomes to the patient involves a process of regulation which aims to ensure safety and efficacy across populations. For many the process is considered unnecessarily lengthy while others consider it to be insufficiently rigorous. The challenge of developing a balanced regulatory framework will be seen through the prism of a number of failed cases where novel pharmaceutical products and medical devices have led to multiparty litigations across jurisdictions. Areas where present regulation fall short of public expectation for safety of medical products will be discussed. The presentation is sponsored C.A.R.E. - the Campaign for Alzheimer’s Research (Europe) of which the author is the founding Trustee.


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DR DERICK MITCHELL The Irish Platform for Patient Organisations, Science and Industry (IPPOSI)

Biosketch: Dr. Derick Mitchell is the Chief Executive of IPPOSI. Derick has over ten years’ experience of management, advocacy, scientific communications and patient/public engagement, through previous positions at both the European and the national level and has a strong interest in the area of patient and public involvement in research. From 2011-2015, Derick was Communications Manager with the EU Joint Programme – Neurodegenerative Disease Research (JPND), where he was responsible for developing external communications strategies and supporting stakeholder engagement activities with patient organisations, researchers and industry across Europe. Derick is a member of a number of national and international boards

including the Health Informatics Society of Ireland (HISI), the EHealth Ireland committee; the oversight committee for the National Rare Disease Plan; the Medical and Life Sciences Committee of the Royal Irish Academy, the International Advisory Board of the HRB-Trials Methodology Research Network; the HIQA Research Ethics & HTA Advisory Boards, among others. Derick graduated with a BSc. (Hons) in Biotechnology from NUI Galway (2000) followed by a PhD in Molecular Medicine from University College Dublin (2004).


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DR RICHARD WYSE The Cure Parkinson’s Trust, England

Biosketch: Dr Richard Wyse joined the Cure Parkinsons Trust in October 2007 as Director of Research and Development. Richard's role within The Cure Parkinson's Trust is to monitor scientific and medical developments into the causes and treatment of Parkinson's disease to design and foster promising new lines of therapeutic research and to promote beneficial worldwide scientific, clinical and new technical collaborations across the Parkinson's community. The Linked Clinical Trials (LCT) programme is his brainchild. Richard also sits on the Research Committee. Richard has an impressive academic record in both laboratory and clinical research. He was senior lecturer in Great Ormond Street Hospital for >20 years, and has also worked extensively at the Brompton and Hammersmith Hospitals in

London. He was recently vice-chairman of the Academic Board and Trustee of the Royal Society of Medicine, as well as its President of Medical Genetics. Commercially, he has been Medical Director of two companies in the UK and USA, and has chaired over 30 international pharmaceutical conferences, published 4 books (on Pharmacoeconomics and Patient Outcomes), and around 120 academic and clinical research papers in a variety of therapeutic areas. He is currently engaged in worldwide basic and clinical research in the development of radical new pharmaceutical and regenerative treatments for Parkinson’s disease, including a major global initiative involving drug repositioning clinical trials to determine relative patient benefits of a large number of different therapeutics in hospitals around the world.

Datablitz Presentations

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Session I: Wednesday 6th December, 15:30 – 16:00

Session Name Country Abstract Title

Session I, Datablitz 1

Andrew Adler

Sweden Synaptic integration of intrastriatal versus intranigral grafts of hESC-

derived neurons in the 6-OHDA-lesioned adult rat brain


Anselme Perrier

Italy MHC matching of iPSC-derived neurons in a non-human primate model of

Huntington’s disease does not prevent long-term allograft rejection


Enrico Bagnoli

Ireland Olfactory bulb slices as a model of pre-motor Parkinson’s disease


Marcella Birtele

Sweden Electrophysiological properties of long term cultured human induced

neurons


Yiki Chen

Scotland Engineering Parkinson’s disease-resistant human dopaminergic neurons

for cell transplantation therapies


Susanne Clinch

Wales Assessing batch variability of GMP-grade hESC-derived DA neurons in a

rat model of Parkinson’s disease

Session II: Thursday 7th December, 10:30 – 11:00


Session II, Datablitz 1

Janelle Drouin-Ouellet

Sweden Modeling of sporadic Parkinson’s disease using directly induced neurons

derived from patients


Charlotte Ermine

Australia Striatal projection neurons are not replaced after ischemic damage


Emma Green

England Do vitamins B3 and D3 protect dopaminergic neurons in an in vitro 6-

OHDA model of Parkinson’s disease?


Francesco Gubinelli

France Mutant form of C-terminal fragment of LRRK2 increases α-synA53T toxicity

in dopaminergic neurons in vivo


Andres Heuer

Sweden Fine-tuning of a stem cell transplant


Deirdre Hoban

Sweden Assessing the integration and function of human embryonic stem cell

derived dopaminergic neurons in a novel -synuclein model of Parkinson’s disease


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Session III: Thursday 7th December, 15:30 – 16:00


Session III, Datablitz 1

Cameron Hunt

Australia Peptide-based scaffolds support human cortical progenitor graft

integration to reduce atrophy and promote functional repair in a model of stroke


Sarah McComish

Ireland The effect of inflammatory cytokines on astrocytes in a human induced

pluripotent stem cell-derived in vitro model of neurodegeneration


Alain Ndayisaba

Austria Iron dyshomeostasis in a mouse model of multiple system atrophy (MSA)


Sara Nolbrant

Sweden Refining stem cell therapy for Parkinson’s disease towards clinical

applications


Justyna Okarmus

Denmark Investigating Parkinson’s disease pathogenesis using induced pluripotent

stem cell-derived neurons carrying PARK2 mutations


Gerard O’Keeffe

Ireland Histone deacetylases as therapeutic targets in Parkinson’s disease.

Session IV: Friday 8th December, 10:30 – 11:00


Session IV, Datablitz 1

Laura Olsen

Ireland A novel Parkinson’s disease model: Combined viral mediated

neuroinflammation and alpha-synuclein aggregation


Ana Rebelo

Ireland Optimisation of a collagen-based delivery system for cell delivery to the

brain


Sinead Savage

England Design of carbon nanomaterials as non-viral vectors for gene therapy of

discrete brain regions by stereotactic surgery


Shelby Shrigley

Sweden Direct reprogramming of adult human fibroblasts: Generation of

dopaminergic neurons for cell-based replacement therapy


Aideen Sullivan

Ireland Inhibition of microRNA-181a promotes midbrain neuronal growth

through a Smad1/5-dependent mechanism: Implications for Parkinson’s disease.


Emma Lane

Wales What does ‘stem cell therapy’ mean to people with Parkinson’s disease?

Datablitz Abstracts

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Datablitz Abstracts Session I, Presentation 1 SYNAPTIC INTEGRATION OF INTRASTRIATAL VERSUS INTRANIGRAL GRAFTS OF HESC-DERIVED NEURONS IN THE 6-OHDA-LESIONED ADULT RAT BRAIN Andrew Adler1,2, Tiago Cardoso1,2, Deirdre Hoban1,2, Sara Nolbrant1,2, Bengt Mattsson1,2, Agnete Kirkeby1,2, Shane Grealis, , and Malin Parmar. 1Developmental and Regenerative Neurobiology, 2Lund Stem Cell Center, Lund University, Sweden Human embryonic stem cell (hESC)-derived neurons survive long-term, release dopamine, and extend axons to fill functionally-appropriate host structures after transplantation into the adult rat brain. Using a monosynaptic rabies virus-based tracing technique, we have recently shown that hESC-derived neurons integrate into host circuitry, establishing both host-to-graft and graft-to-host synaptic connections (Grealish et al., 2015). Here, we use the same methodology to further investigate the connectivity of midbrain- and forebrain-patterned hESCs-derived neurons transplanted either to the striatum or substantia nigra of 6-OHDA-lesioned rats. To assess for host-to-graft synaptic connectivity, animals were injected with modified rabies virus 23 weeks after transplantation, and were perfused one week later. Analysis 24 weeks post-grafting revealed that both local and distant host neurons made extensive synaptic contacts onto both intrastriatal and intranigral grafts. The gross anatomical location of host cells labelled with rabies varied more depending on the location of transplantation, than on the phenotype of the cells grafted. Further, we have identified host neurons making monosynaptic contacts onto graft-derived neurons which express molecular markers of cells that participate in canonical circuits of the basal ganglia. In summary, we show that intrastriatal and intranigral grafts of hESC-derived neurons can integrate into host circuitry, and that the pattern of host connectivity is primarily dependent on location of the transplant. References: Grealish, Shane, et al. "Monosynaptic tracing using modified rabies virus reveals early and extensive circuit integration of human embryonic stem cell-derived neurons." Stem cell reports 4.6 (2015): 975-983. Acknowledgements: We gratefully acknowledge support from the European Community's Seventh Framework Programme, the Strong Research Environment at Lund University Multipark, the Swedish Research Council, the Swedish Society for Medical Research, the UK Regenerative Medicine Platform and Innovation Fund Denmark, and the New York Stem Cell Foundation. MP is a New York Stem Cell Foundation Robertson Investigator.

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Session I, Presentation 2 MHC MATCHING OF IPSC-DERIVED NEURONS IN A NON-HUMAN PRIMATE MODEL OF HUNTINGTON’S DISEASE DOES NOT PREVENT LONG-TERM ALLOGRAFT REJECTION Romina Aron Badin1,2, Aurore Bugi3, Susannah Williams1,2, Marta Vadori6, Marie Michael3, Caroline Jan1,2, Alberto Nassi1,2, Sophie Lecourtois1,2, Emanuele Cozzi7, Philippe Hantraye1,2, Anselme L Perrier4,5. 1CEA, DRF, Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France; 2CNRS, CEA, Paris-Sud Univ., Univ. Paris-Saclay, Neurodegenerative Diseases Laboratory (UMR9199), 92265, Fontenay-aux-Roses, France; 3CECS, I-STEM, AFM, Corbeil-Essonnes 91100 France; 4Inserm U861, I-STEM, AFM, Corbeil-Essonnes 91100 France; 5UEVE U861, I-STEM, AFM Corbeil-Essonnes 91100, France; 6CORIT, Ospedale Giustinianeo, Padova, ITALY, Padova, Italy; 7Transplantation Immunology Unit, Padua University Hospital, Padova, ITALY Matching haplotypes of iPSC donors (HLA homozygous lines) and patient opens up opportunities to secure scalable sources of cell therapy products (CTP) with enhanced or full immunological compatibility. Recent experiments have shown that major histocompatibility complex (MHC) matching could be a solution for allogeneic stem cell transplantation in the retina#1 and in the striatum#2 of non-lesioned non-human primates (NHP) without immunosuppressive medication at 6 and 4 months post-transplantation, respectively. Here we present a study in which we challenged the efficacy of MHC matching in long-term allograft rejection in a NHP model of Huntington’s disease. We performed a comparative assessment of the immunogenicity of autologous, haplotype-matched and two-haplotype mismatched neuronal grafts in the excitotoxically-lesioned striatum of NHP. First, blood cells from different NHPs homozygous for MHC Class I&II were used to produce several iPSC lines that were subsequently differentiated into striatal cells. Next we assessed their potential immunogenicity at 3 and/or 6 months after intra-striatal grafting in haplotype mis-matched, matched and autologous NHP recipients. Our results suggest that, unlike autologous neuronal grafts, allogenic and haplotype-matched grafts elicit a local infiltration of CD8+ T cells, CD68+ macrophages cells and an increase in local Iba1 and HLA-DR staining. Serum levels of antibodies against all 3 types of graft cells and their ability to trigger complement dependent cytotoxicity (CDC) in vitro was measured longitudinally to monitor the humoral response elicited by the graft. None of the transplant combinations elicited any significant increase in the serum levels of anti-graft antibodies or CDC activity at any time after transplantation. In the specific context of transplantation in the brain, our pre-clinical data suggest that, as for solid organ transplantation, HLA matching alone is insufficient to grant longterm graft survival but could be a cost effective compromise to reduce peripheral immunosuppression and its side effects in the clinical setting. References: #1: Sugita et al (2016) Stem cell reports #2: Morizane et al (2017) Nat Comm. Acknowledgements: This work was supported by grants from Agence Nationale pour la Recherche: HD-SCT ANR-2010-RFSC-003, NeurATRIS ANR-11-INBS-0011, Labex REVIVE ANR-10-LABX-73 and the European Union's 7th Framework Programme Repair-HD, nr. 602245

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Session I, Presentation 3 OLFACTORY BULB SLICES AS A MODEL OF PRE-MOTOR PARKINSON’S DISEASE Enrico Bagnoli, Alexandre Trotier, Jill McMahon, Una FitzGerald. CÚRAM Centre for Research in Medical Devices, National University of Ireland, Galway, Ireland. Parkinson’s disease (PD) is the second most common neurodegenerative disease, affecting more than 10 million people worldwide. In order to achieve a better understanding of the disease and to develop new effective therapeutics, an important step is the creation of a reliable model of the disease. In this sense, organotypic brain slices can be a useful tool combining the main advantages of in vivo studies with the excellent experimental accessibility of in vitro models. In particular olfactory bulb slices can enable researchers to understand the early stage of the pathology, before the disease affects other regions of the brain. The overarching goal of the project is to induce α-synuclein aggregation using DOPAL in olfactory bulb slices to mimic pre-motor PD and to study the effect of iron on the slices. Slices have been successfully obtained and kept alive for more than 3 weeks and culture conditions have been optimised. Preliminary studies suggest that DOPAL incubation impairs viability and structural integrity of the slices in a dose dependent way and an increase in the nitrite content of the media is associated with increasing doses of DOPAL. Olfactory bulb slices show great promise as an easy, accessible and simple platform for new PD’s treatment development. References: Healy et al, Significant glial alterations in response to iron loading in a novel organotypic hippocampal slice culture model. Jinsmaa et al., Divalent metal ions enhance DOPAL-induced oligomerization of alpha-synuclein. Matute et at., Utility of Organotypic Slices in Parkinson’s Disease Research, Towards New Therapies for Parkinson’s Disease. Acknowledgements: This project has been funded by the European Union Horizon 2020 Programme (H2020-MSCA-ITN-2015) under the Marie Skłodowska-Curie Innovative Training Networks and Grant Agreement No. 676408.

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Session I, Presentation 4 ELECTROPHYSIOLOGICAL PROPERTIES OF LONG TERM CULTURED HUMAN INDUCED NEURONS Birtele M., Drouin-Ouellet J., Rylander-Ottosson D., Parmar M. Developmental and Regenerative Neurobiology, Wallenberg Neurocenter, Lund University, Sweden. Induced neurons (iNs) are reprogrammed somatic cells that are forced to change their fate without passing through a pluripotent state, shortening the process of neuronal generation compared to the use of human pluripotent stem cells. The scientific interest in these cells is due to their suitable use for disease modelling, drug screening and cell therapy for diseases such as Parkinson Disease (PD). An important characteristic of the reprogrammed cells that has to be taken into account to confirm their neuronal identities is their electrophysiological profile. Here, we aim at studying the electrical activity of iNs using the whole cell patch-clamp technique. We evaluate how the delivery of different transcription factors (TFs) through a lentivirus system induces neuronal maturation. More specifically, we compare the electrophysiological profile of the iNs generated by a combination of Ascl1, Brain2, Myt1L, NeuroD1, Lmx1, Foxa2, Otx2, Nurr1 and REST inhibition at different time points. The result shows active iNs after 50 days of culture, with presence of immature, intermediate and mature action potentials induced by steps of current depolarisation. The physiological parameters analysed shows a progressive maturation of the iNs that result to be spontaneously active after 90 days of culture. This result is an important step in the use of the iNs both for disease modelling and cell transplantation since it indicates that they mature into functional neurons.

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Session I, Presentation 5 ENGINEERING PARKINSON’S DISEASE-RESISTANT HUMAN DOPAMINERGIC NEURONS FOR CELL TRANSPLANTATION THERAPIES Yixi Chen1, Karamjit Singh Dolt1, Nicola J Drummond1, Ammar Natawala1, Susan Rosser2, Tilo Kunath1. 1MRC Centre for Regenerative Medicine, The University of Edinburgh, Edinburgh, UK. 2UK Centre for Mammalian Synthetic Biology, The University of Edinburgh, Edinburgh, UK. Parkinson’s disease (PD) is characterised by the massive loss of dopaminergic neurons that originate in the substantia nigra and innervate the striatum. A cell replacement therapy that involved transplantation of human fetal ventral mesencephalic tissue into patients’ striatum worked well in some cases1, but Lewy bodies (LBs), the hallmark of PD, were found in the grafted neurons of patients who died 11-24 years after transplantation2,3. LBs contain large amounts of aggregated α-synuclein (αSyn) protein, and it is thought that host-to-graft transfer of pathogenic αSyn is responsible for LBs in the grafts. Preventing or reducing aggregation of αSyn within the graft will improve the function and longevity of future cell-based therapies for PD. Here we have used synthetic biology tools to manipulate the αSyn gene in human embryonic stem cells (hESCs) in an effort to produce pathology-resistant neurons. We have taken two approaches: the first is to use CRISPR/Cas9 to remove a critical exon of the human αSyn gene, as the formation of LB-like aggregates relies on the presence of endogenous αSyn. The second approach is to use homology-directed repair to introduce point mutations into αSyn that reduces or eliminates the ability of the protein to oligomerise and aggregate, without disturbing the potential normal biological function of αSyn. These genetically-engineered hESC lines will be differentiated into midbrain dopaminergic neurons and challenged with αSyn preformed fibrils (PFFs). The exogenous αSyn PFFs act as seeds to recruit soluble cytoplasmic αSyn, which go on to form large aggregates in wild-type neurons4. This assay will be used to investigate whether neurons with no or altered αSyn are susceptible to PFF-induced pathology. References: 1. Li, W, et al. (2016) Extensive graft-derived dopaminergic innervation is maintained 24 years after transplantation in the degenerating parkinsonian brain. Proc Natl Acad Sci USA, 113:6544-9. 2. Kordower, JH, et al. (2008) Lewy body–like pathology in long-term embryonic nigral transplants in Parkinson's disease. Nat Med, 14:504-6. 3. Li, J-Y, et al. (2008) Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation. Nat Med. 14:501-3. 4. Luk, KC, et al. (2009) Exogenous α-synuclein fibrils seed the formation of Lewy body-like intracellular inclusions in cultured cells. Proc Natl Acad Sci USA, 106:20051-56.

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Session I, Presentation 6 ASSESSING BATCH VARIABILITY OF GMP-GRADE HESC-DERIVED DA NEURONS IN A RAT MODEL OF PARKINSON'S DISEASE Susanne P. Clinch1, David Harrison1, Stephen B. Dunnett1, Roslin Cell Therapies2, Agnete Kirkeby2,3, Malin Palmar2,3, and Mariah J. Lelos1. 1School of Biosciences, Cardiff University; 2Roslin Cell Therapies, Edinburgh; 3Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University. Sweden. Neural transplantation using ESC-derived grafts is a potential therapy for people with Parkinson’s disease. However, standardized GMP-grade cells are required for this to move into clinic (1). The aim of this study was to assess between batch reproducibility and reliability of GMP-grade hESC-derived DA neurons in the Parkinsonian rat. Three GMP-grade batches of cell therapy product (CTP) were produced using an identical protocol by Roslin Cell Therapies. Sprague dawley rats (n=76) received 6-hydroxydopamine unilateral lesions into the MFB. Rats either remained as lesion-only (n=10) or received intrastriatal transplants of hESC-derived DA neurons from one of three batches (n=22 per group; T07, T08 and T09). All rats were tested for motor dysfunctions one-week post-lesion, which included cylinder, vibrissae, stepping and amphetamine rotations. An early group was perfused for histological analysis 10 weeks post-graft. The remaining rats were behaviourally tested monthly between 12-24 weeks post-graft. Rats also had apomorphine rotations 20 and 24 weeks post-graft, and perfused at 25 weeks for histological analysis. Results revealed that the T07 batch ameliorated rotational deficits earlier than the T08 or T09 batches. This batch also produced larger grafts, containing 54.7% TH positive cells relative to the lesion-only and T08 and T09 groups 10 weeks post-graft. Hand testing performance revealed no difference across any group. Behavioural results 24 weeks post-graft and histology from the remaining rats perfused 25 weeks will be presented at the conference. Molecular analyses of the CTP batches will seek to identify relevant markers that correlate with the optimal batch outcome. In order to progress ESC-derived DA cell therapies to the clinic, it is critical to ensure the consistent production of GMP-grade CTPs and to identify relevant markers of batch success. References: 1. Kirkeby et al, 2017. Cell stem cell, 20(1), pp.135-148. Acknowledgements: This study was supported by EU FP7 NeuroStemcellRepair.

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Session II, Presentation 1 MODELING OF SPORADIC PARKINSON’S DISEASE USING DIRECTLY INDUCED NEURONS DERIVED FROM PATIENTS 1Drouin-Ouellet J., 1Pircs K., 1Perreira M., 1,2Barker RA. and 1Parmar M. 1Department of Experimental Medical Science, Wallenberg Neuroscience Center, Division of Neurobiology and Lund Stem Cell Center, Lund University, BMC A11, S-221 84 Lund, Sweden. 2John van Geest Centre for Brain Repair & Department of Neurology, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Cambridge, CB2 0PY. Directly reprogrammed neurons (induced neurons; iNs) hold great promise for disease modeling of neurodegenerative disorders associated with aging as they maintain some of the signature associated with age from the parental cells. As such, they could also express the intra-cellular disease associated features occurring in idiopathic forms of Parkinson’s disease (PD). Here, we investigate mitochondrial dysfunctions as well as autophagy alterations in iNs derived form PD patient’ skin fibroblasts. More specifically, we show that iNs from PD patients have an increased superoxide production and neuronal death in response to a rotenone challenge. Furthermore, iNs from PD patients depict p62 protein accumulation and a decrease in LC3+ vesicle size as compared to matched healthy donors. These results suggest an increased neuronal vulnerability to oxidative stress as well as protein degradation alteration, two features that are believed to participate to the pathophysiology of PD. This study thus shows the usefulness of iNs to generate models of sporadic forms of PD using patient-derived material, which will serve as an invaluable tool for therapeutic target identification and drug screening assays.

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Session II, Presentation 2 STRIATAL PROJECTION NEURONS ARE NOT REPLACED AFTER ISCHEMIC DAMAGE Charlotte M. Ermine1, Jordan L. Wright1,2, Clare L. Parish1 and Lachlan H. Thompson1. 1The Florey Institute for Neuroscience and Mental Health, The University of Melbourne, Australia and 2Current address: Wolfson Institute for Biomedical Research, University College London, UK Neurogenesis from the subventricular zone (SVZ) is increased after striatal ischemia in both adult and neonatal rats. Under normal conditions the adult SVZ generates interneurons that migrate to the olfactory bulb, while the neonatal SVZ generates both interneurons and medium spiny neurons (MSN), the main neuronal subtype affected after striatal ischemia. In addition, it was reported that the adult brain is capable of redirecting SVZ progenitors to the injury site and reprogram their fate to become MSN [1]. These results suggested an attempt of the brain to repair itself and stimulated research into successful ‘endogenous cell therapies’. However, few years later conflicting results reported that the adult brain was in fact not capable of generating MSN after ischemia, thus reconsidering the real potential of endogenous cell therapies [2]. In this study, we aimed at comparing the adult and neonatal brain after striatal ischemia, by investigating proliferation, neurogenesis levels and progenitors’ phenotypes. The results showed that while the neonatal brain was producing MSN, the production rate was not increased by the injury. In addition, the results showed that the adult brain only generates interneurons in response to injury. This suggests that while endogenous cell replacement therapies are attractive, many factors including neurogenesis rate and neuronal fate, need to be manipulated in order to have a successful treatment for brain injury such as stroke. References: [1] A. Arvidsson, T. Collin, D. Kirik, Z. Kokaia, and O. Lindvall, “Neuronal replacement from endogenous precursors in the adult brain after stroke,” Nat Med, vol. 8, no. 9, pp. 548–553, 2002. [2] F. Liu et al., “Brain injury does not alter the intrinsic differentiation potential of adult neuroblasts,” J. Neurosci., vol. 29, no. 16, pp. 5075–5087, 2009. Acknowledgements: The authors thank Mong Tien for expert technical assistance in the tissue preparation and immunohistochemical procedures.

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Session II, Presentation 3 DO VITAMINS B3 AND D3 PROTECT DOPAMINERGIC NEURONS IN AN IN VITRO 6-OHDA MODEL OF PARKINSON’S DISEASE? Emma L. Green1,2, Yasemin Zaremba2, Rosemary Fricker2 and Stuart I. Jenkins2. 1ISTM, University of Keele, UK and 2School of Medicine, University of Keele, UK. Vitamin levels are implicated in numerous neurodegenerative diseases including Parkinson’s disease. The neuroprotective potential of vitamin D3 is well documented, whilst vitamin B3 is gaining popularity as a possible neuroprotectant and stimulator of neurogenesis, though there is speculation that diets high in vitamin B3 could be deleterious1. Our research group has shown the protection of primary dopamine neurons through addition of 10 nM calcitriol (an active metabolite of vitamin D3)2 and neural-directed differentiation of embryonic stem cells through 10 mM nicotinamide (a form of B3)3. This project aims to assess the effects of calcitriol and nicotinamide on an in vitro model of Parkinson’s disease. Primary E12 rat substantia nigra cultures were maintained for 7 days either with 10 nM calcitriol, 10 mM nicotinamide, both vitamins in combination or no vitamins present. Cultures were then treated for 15 minutes with 6-hydroxydopamine (6-OHDA) in 0.015% ascorbic acid vehicle or ascorbic acid vehicle alone, and fixed at 48 h. Immunocytochemistry was used to identify neurons (β-III-tubulin) and dopaminergic neurons (tyrosine hydroxylase, TH). Preliminary results showed that 6-OHDA specifically reduced TH+ cells. Calcitriol protected TH+ cells from 6-OHDA toxicity, and increased total cell and neuron number. However, 10 mM nicotinamide showed toxic effects both morphologically and quantitatively, reducing total cell, neuron and dopamine neuron numbers. Continuing work will test a range of nicotinamide concentrations to establish the level of benefit and toxicity to primary substantia nigra neuronal cultures. References: 1. Williams, A. & Ramsden, D. Parkinsonism Related Disorders. 11(7), 412-420, (2005); 2. Orme et al. PLOS ONE. 8(4), e62040, (2013); 3. Griffin et al. PLOS ONE. 12(8), e0183358, (2017). Acknowledgements: Thanks to Matthew Dunn and Natasha Hill for assistance with cell culture and data collection.

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Session II, Presentation 4 MUTANT FORM OF C-TERMINAL FRAGMENT OF LRRK2 INCREASES Α-SYNA53T TOXICITY IN DOPAMINERGIC NEURONS IN VIVO Francesco Gubinelli, Noémie Cresto, Marie-Claude Gaillard, Gwenaëlle Auregan, Martine Guillermier, Camille Gardier, Charlène Josephine, Fanny Petit, Caroline Jan, Pauline Gipchtein, Noëlle Dufour, Philippe Hantraye, Géraldine Liot, Alexis Pierre Bemelmans, Emmanuel Brouillet. CEA, DRF, Institute François Jacob, Molecular Imaging Research Center (MIRCen), CNRS, CEA, Paris-Sud Univ., Univ. Paris-Saclay, Neurodegenerative Diseases Laboratory (UMR9199), Fontenay-aux-Roses, France. Alpha-synuclein (α-syn) and leucine-rich repeat kinase 2 (LRRK2) are two proteins that play crucial roles in both sporadic and familial forms of Parkinson’s disease (PD). Recent data suggest the existence of an interplay between these two proteins in the pathogenesis of PD. In the present study

we hypothesized that the C-terminal part of LRRK2 (LRRK2) containing the kinase domain could behave, at least in part, as the full form of LRRK2 and trigger neurodegeneration when overexpressed using adeno associated virus (AAV) in substantia nigra pars compacta (SNc) neurons. Our results

showed that the kinase activity of LRRK2 is similar to that of the full lenght protein, and that, at 25

weeks post injection in the rat SNc, AAV-LRRK2G2019S led to a moderate but significant loss of

dopaminergic neurons (DA) (~30%) while AAV coding for the wild type (WT) form of LRRK2 did not.

We also investigated whether overexpression of LRRK2G2019S could modify the toxicity of α-

synA53T. Results showed that using AAVs, the majority of DA neurons co-expressed both LRRK2 (WT or G2019S) and α-synA53T. Such co-expression produced greater loss of DA neurons when compared

with α-synA53T alone at the time point post-infection (15 weeks) whenLRRK2G2019S alone was not

toxic. This effect was not seen with the dead kinase (DK) form of LRRK2G2019S. Since it has been suggested that the level of expression of LRRK2G2019S may play a key role in its toxicity, we checked using quantitative confocal microscopy that WT, GS and DK forms of LRRK2 were at similar levels of expression in all the analysed conditions. The present results suggest that overexpression of the mutant kinase domain of LRRK2 is sufficient to trigger neurodegeneration and increase α-synA53T toxicity in DA neurons in vivo. The presence of LRRK2G2019S in SNc neurons could render neurons more vulnerable to α-syn in PD. References: Lesage & Brice, Parkinson’s disease: From monogenic forms to genetic susceptibility factors. Human Molecular Genetics 18, (2009). Acknowledgements: This work was funded by rolling grants from the CEA and the CNRS. The research generating these results received funding from la Fondation de France (AAP 2010-12, Engt 16819) and Association France Parkinson (2016). Francesco Gubinelli is a recipient of a PhD fellowship from the European Union Horizon 2020 Programme (H2020-MSCA-ITN-2015) under the Marie Skłodowska-Curie Innovative Training Networks and Grant Agreement No. 676408. This work benefited from a support from the national “Translational Research Infrastructure for Biotherapies in Neurosciences” (NeurATRIS, “Investissement d'Avenir”, ANR-11-INBS-0011).

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Session II, Presentation 5 FINE-TUNING OF A STEM CELL TRANSPLANT Andreas Heuer1, Marcus Davidsson1, Sara Nolbrant2, Patrick Aldrin-Kirk1, Tim Fieblinger3, Martin Lundblad2, Agnete Kirkeby4, Malin Parmar2, Tomas Björklund1. 1Molecular Neuromodulation, Lund University, Lund , Sweden; 2Developmental and Regenerative Neurobiology, Lund University, Lund, Sweden; 3Basal Ganglia Pathophysiology, Lund University, Lund, Sweden; 4Human Neuronal Development, Lund University, Lund , Sweden. Dopaminergic human embryonic stem cells (hESCs) are currently being developed for cell replacement therapy in Parkinson’s disease. As behavioural recovery on many behavioural tests in preclinical rodent models is often incomplete or excessive we aim to selectively fine-tune the dopamine release from the transplanted cells by introducing on-off switches into the hESCs. We desensitised neonatal rat pups with hESCs in order to accept future transplantation of human tissue. The adult rats were then subjected to a series of behavioural tests before and after receiving unilateral 6-OHDA lesions. Then we engrafted dopaminergic, Cre-expressing hESCs into the denervated striatum. After maturation of the graft we used Cre-inducible vector systems to selectively express chemogenetic receptors in the transplanted cells only. We used behavioural, electrochemical and histological readout to investigate the function of the graft. hESC survived long-term (>52 weeks), differentiated into dopaminergic cells of a midbrain phenotype, and were able to ameliorate the lesion-induced deficits. We were able to induce dopamine-release from the transplanted cells via activation of the chemogenetic receptors.

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Session II, Presentation 6 ASSESSING THE INTEGRATION AND FUNCTION OF HUMAN EMBRYONIC STEM CELL DERIVED

DOPAMINERGIC NEURONS IN A NOVEL -SYNUCLEIN MODEL OF PARKINSON’S DISEASE Deirdre B. Hoban1,3,4, Ludivine S. Breger2, Jenny Nelander Wahlestedt1,3, Tiago Cardoso1,3, Bengt Mattsson2, Kelvin J. Luk4, Virginia M. Y. Lee4, John Q. Trojanowski4, Anders Björklund2 and Malin Parmar1,3. 1Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center, Lund University, Sweden; 2Neurobiology, Department of Experimental Medical Science, Lund University, Sweden; 3Lund Stem Cell Center, Lund University, Sweden; 4Department of Pathology and Laboratory Medicine, University of Pennsylvania, PA, USA. Preclinical validation studies to assess the therapeutic potential of human embryonic stem cell (hESC) derived dopaminergic (DA) neurons have mostly been performed in the 6-hydroxydopamine (6-OHDA) model of Parkinson’s disease (PD). However, this model does not reflect the pathological features or progressive nature of PD. Here, we aim at assessing how the transplanted cells mature, integrate and

innervate the existing circuitry in a novel combined model of PD, whereby preformed human -

synuclein fibrils and AAV6 human -synuclein are unilaterally injected into the rat substantia nigra.

This model gives rise to -synuclein pathology, inflammation and progressive loss of DA cells from the substantia nigra and terminals in the striatum. After allowing the model to develop for 8 weeks, we then transplanted hESC-derived DA neurons into the striatum and assessed their maturation, integration and innervation at 6 weeks post-transplant. Post mortem histology revealed that transplanted cells were capable of innervating the dopamine depleted striatum in a similar, biologically-relevant pattern previously seen in the 6-OHDA model. We also determined (using monosynaptic tracing based on the modified rabies virus) that the pathology present in this model did not inhibit the ability of the graft to integrate into the host circuitry, meaning that the grafted cells are able to receive appropriate and sufficient synaptic contact with the host central nervous system.

Finally, on closer examination, we found preliminary evidence of -synuclein pathology in the grafted

region of the striatum, indicating that possible host-to-graft transfer of -synuclein pathology. Further studies to confirm this observation, and to examine a longer time-point where we can assess the maturation and function of the transplanted cells, and if this is affected by the potential pathology transfer, are currently underway. This will give us a better understanding of the performance of these

cells in a more clinically relevant, novel -synuclein model of PD, thus adding to the body of knowledge required as this cell replacement therapy progresses to clinical trials.

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Session III, Presentation 1 PEPTIDE-BASED SCAFFOLDS SUPPORT HUMAN CORTICAL PROGENITOR GRAFT INTEGRATION TO REDUCE ATROPHY AND PROMOTE FUNCTIONAL REPAIR IN A MODEL OF STROKE Cameron Hunt & Clare Parish. Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia. Stem cell transplants offer significant hope for repairing the stroke injured brain. Pre-clinical work suggests that therapeutic mechanisms may be multi-faceted – incorporating bone-fide circuit reconstruction by transplanted neurons, but also protection/regeneration of host circuitry. Here we bioengineered hydrogel scaffolds to form “bio-bridges” within the necrotic lesion cavity, providing physical and trophic support to transplanted human embryonic stem cell-derived cortical progenitors, and residual host neurons. Scaffolds were fabricated by the self-assembly of peptides for a laminin-derived epitope, thereby mimicking the brain’s major extracellular protein. Following focal ischemia in rats, scaffold-supported cell transplants induced progressive motor improvements over 9 months, compared to Cell- or scaffold-only implants. These grafts were larger, exhibited greater neuronal differentiation and showed enhanced electrophysiological properties reflective of mature, integrated neurons. Varying graft timing post-injury enabled us to attribute repair to both neuroprotection and circuit replacement. These findings highlight strategies to improve efficiency of stem cell grafts for brain repair.

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Session III, Presentation 2 THE EFFECT OF INFLAMMATORY CYTOKINES ON ASTROCYTES IN A HUMAN INDUCED PLURIPOTENT STEM CELL-DERIVED IN VITRO MODEL OF NEURODEGENERATION Sarah F. McComish, Ibel C. Fredy, Noreen Boyle, Maeve A. Caldwell. Department of Physiology, Trinity College Dublin, Dublin, Ireland Emerging evidence supports a detrimental role of astrocytes in neurodegeneration, with Liddelow and colleagues1 classifying reactive astrocytes as inflammatory or protective, similar to previous classification of macrophages/microglia. We aimed to examine this classification in human iPS cells derived from adult somatic cells which can be patterned into numerous cell types. The ability to derive astrocytes and neurons from iPS cells provides a useful in vitro model of CNS disorders. Human iPS cells were patterned towards a neural fate using SB431542, LDN193189, SHHC24II and CHIR99021. Neural progenitors were matured using DAPT and cAMP dibutyryl to derive mature neurons. Alternatively astrocytes were derived following a protocol developed by Serio and colleagues2 using epidermal growth and human leukemia inhibitory factors to produce mature astrocytes after 90 days. Astrocytes reactivity was induced (IL-1α, TNFα and C1q)1 and the effect of FGF2 on reactivity was examined. Stimulation with cytokines resulted in increased astrocyte reactivity indicated by increased GFAP expression and IL-6 secretion. qPCR analysis of ptx3, amigo2 and gvinp1 indicated a trend towards reactivity following treatment with cytokines and a potential for FGF2 to reduce this reactivity. ACM from reactive astrocytes diminished neuronal health indicated by increased γH2AX+ cells in treated cultures. FGF2 tends to reduce this toxic effect with a reduction in γH2AX+ cells treated with ACM from astrocytes stimulated with cytokines and FGF2. The ability to produce reactive astrocytes in vitro in human cell lines provides a powerful model for researching disorders of the CNS. References: 1. Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017;541(7638):481-7. 2. Serio A, Bilican B, Barmada SJ, Ando DM, Zhao C, Siller R, et al. Astrocyte pathology and the absence of non-cell autonomy in an induced pluripotent stem cell model of TDP-43 proteinopathy. Proc Natl Acad Sci U S A. 2013;110(12):4697-702.

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Session III, Presentation 3 IRON DYSHOMEOSTASIS IN A MOUSE MODEL OF MULTIPLE SYSTEM ATROPHY (MSA) A. Ndayisaba1*, C. Kaindlstorfer1*, M. Seifert2, N. Stefanova1, G. Weiss2, G. K. Wenning1. 1Department of Neurology, Division of Neurobiology, Medical University Innsbruck, Austria; 2Department of Internal Medicine, Medical University Innsbruck, Austria. *Contributed equally Background: Iron is essential for cellular development and maintenance of multiple physiological processes in the central nervous system. However, disturbance of its homeostasis leads to abnormal deposition in the brain and causes neurotoxicity via generation of free radicals and oxidative stress. Oxidation of iron to its ferric isoform leads to aggravation of α- syn pathology. Contrary to Parkinson’s disease, its contribution in the pathogenesis of multiple system atrophy (MSA) is to be elucidated. Objective: The aim of this study was to evaluate iron levels and iron related proteins in association to age of transgenic MSA and wildtype mice. Methods: Transgenic (Tg) PLP-α-SYN mice and C57/black 6 mice wildtype (wt) mice aged 2, 5, and 13 months (M) were used. Western blot analyses targeting ferroportin (FP), transferrin receptor (TfR1), divalent metal transporter 1 (DMT1) hepcidin (HP), and tissue iron (Fe) were performed in the striatum of animals. Histochemical work up included ferrocyanid-DAB stain to visualize toxic ferric iron on microtome cut brain sections. Stereological counting of intensely and weakly stained cells in substantia nigra pars compacta (SNpc) based on optical density cut-off (55 luminance) in tg PLP-α-syn mice versus wt mice was performed. Results: Tg MSA mice at age 2 M revealed significantly more tissue iron in striatum versus controls, whereas tissue iron levels at age 5 M and 13 M were comparable. Plus, FP, TfR1, HP levels were significantly decreased at age 2 M and 5 M. DMT1 levels did not differ in any age group. Tg and wt mice aged 13 M differed significantly in FP and TfR1 levels, whereas HP levels levelled off within the range of health controls, as did tissue iron in the 13 M tg group, albeit displaying a nonsignificant trend towards the tg group. Analysis of ferrocyanid-DAB stained brain sections exhibited remarkably increased iron accumulation in the tg group of mice at age 2 M and 13M. Conclusion: Our results support the idea that iron dyshomeostasis constitutes an integral part in MSA pathogenesis. Iron chelators might pose a potent disease modifying therapy to be tested in clinical trials.

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Session III, Presentation 4 REFINING STEM CELL THERAPY FOR PARKINSON’S DISEASE TOWARDS CLINICAL APPLICATIONS Sara Nolbrant1,2, Agnete Kirkeby1,2, Katarina Tiklova3,4, Shane Grealish1,2, Andreas Heuer1,2, Tiago Cardoso1,2, Mariah Lelos5, Stephen Dunnett5, Thomas Perlmann3,4, Malin Parmar1,2. 1Department of Experimental Medical Science, Wallenberg Neuroscience Center, Lund University, Sweden, 2Lund Stem Cell Center, Lund University, Sweden, 3Ludwig Institute for Cancer Research, Stockholm, Sweden, 4Department of Cell and Molecular Biology, Karolinska Institutet, Sweden, 5Brain Repair Group, School of Bioscience, Cardiff University, UK Stem cell based treatments for a number of neurodegenerative diseases are being developed and expected to reach clinical trials within a few years. A major challenge when developing such therapies is that transplantation is performed with immature progenitors which undergo final differentiation and functional maturation after transplantation, and no markers predicting functional efficacy in vivo exist today. To address this issue we performed a comprehensive retrospective analysis of past grafting experiments, to compare in vivo outcomes in terms of graft volumes, dopaminergic (DA) cell numbers and DA cell densities. We then took an unbiased approach to identify early markers that predict successful graft outcomes of transplanted DA progenitors in an animal model of Parkinson’s disease. Through RNAseq analysis of >30 batches of hESC-derived progenitors, we identified novel markers restricted to the caudal part of the VM that correlate with a successful grafting outcome. These markers were then used to develop a GMP-compatible cell differentiation protocol which can be efficiently used on many different hESC-lines, producing a cell product for direct transplantation or for cryopreservation and transplantation upon demand. This study presents a critical step forward for the pre-clinical work of securing the safety and efficacy of the transplantable cell product.

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Session III, Presentation 5 INVESTIGATING PARKINSON’S DISEASE PATHOGENESIS USING INDUCED PLURIPOTENT STEM CELL-DERIVED NEURONS CARRYING PARK2 MUTATIONS Justyna Okarmus, Sissel Schmidt, Matias Ryding, Helle Bogetofte and Morten Meyer. Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, DK Mutation of the gene PARK2, which encodes an E3 ubiquitin ligase, is the most common cause of early-onset Parkinson's disease (PD). Mitochondrial dysfunction is associated with the pathogenesis of both familial and sporadic PD1,2. The advent of the induced pluripotent stem cell (iPSC) technology allows generation of iPSCs from PD patient fibroblasts, which subsequently can be differentiated into dopaminergic neurons3. Using human iPSCs, the aims of the present study were to investigate the effects of PARK2 mutations on cell proliferation, viability, neuronal differentiation and mitochondrial morphology. PARK2 knock out (KO) and isogenic control iPSC-derived neural stem cells were propagated and differentiated into tyrosine hydroxylase-positive cells. Differences in cell proliferation and mitochondrial morphologies were analysed using various biochemical assays, cell counts and electron microscopy. Cell counts and viability assays showed decreased proliferation rate and viability for PARK2 KO cells compared to isogenic controls. Following differentiation, immunostaining and analysis revealed similar yields of dopaminergic neurons in both groups (approx. 25 % of total cells). Immunofluorescence staining for the outer mitochondrial membrane protein TOM20, transmission electron microscopy and subsequent quantitative analyses revealed a significant increase in total mitochondrial area and number of elongated mitochondria in PARK2 KO cultures compared to healthy controls. We have shown that PARK2 mutations cause phenotypic changes in human iPSC-derived neurons in vitro. Furthermore, mitochondrial analyses have indicated impaired mitophagy and disrupted balance between mitochondrial fusion and fission processes for neurons with PARK2 mutations. References: 1. Zanellati et al. Front Genet. 2015; 6: 78. 2. Shaltouki et al. Stem Cell Rep. 2015; 4(5): 847–59. 3. Cooper et al. Sci Transl Med 2012; 4(141): 141–90. Acknowledgements: The project is funded by the Innovation Fund Denmark (BrainStem), the Lundbeck Foundation and the Danish Parkinson Foundation.

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Session III, Presentation 6 HISTONE DEACETYLASES AS THERAPEUTIC TARGETS IN PARKINSON’S DISEASE. Gerard W. O’Keeffe1, Erin M. McCarthy1, Martina M. Mazzocchi1, Louise M. Collins1,2 and Aideen M. Sullivan1. 1Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland. 2Department of Biological Sciences, Cork Institute of Technology, Cork, Ireland. Functional decline in Parkinson’s disease (PD) is the cumulative result of regulatory alterations affecting large numbers of genes involved in various aspects of neuronal maintenance and function. Central to this is the regulation of transcription by enzymes known as histone deacetylases (HDAC) which promote the de- -synuclein binds

-synuclein reduces acetylated histone 3 (AcH3) levels. Here we used a network approach to identify all genes that had a significant positive (r+) or negative (r-) correlation with the expression of all HDACs using microarray data from the human substantia nigra (SN; GSE 60863). We then conducted a detailed enrichment analysis to identify biological pathways that over-represented and may be linked to PD. These analyses showed that Class-II but not Class-I HDACs were significantly correlated with functional pathways linked to PD (p<0.0001). These included genes linked to familial PD and oxidative phosphorylation, including those associated with mitochondrial complex I. To determine if class-specific HDAC inhibition was a viable therapeutic approach, we first examine a range of HDAC inhibitors for their ability to promote axonal growth and branching in SH-SY5Y cells given the progressive axonal degeneration in PD1. We found that a MC1568 (a class II inhibitor) but not MS275 (a class I inhibitor) promoted significant increases in axon growth and branching (p<0.01). Therefore we further examined the therapeutic potential of MC1568, and found it protected against the detrimental effects of MPP+-induced axonal degeneration in a number of in vitro models of PD. This study therefore provides insights into the regulator mechanisms that may control gene expression linked to PD, and highlights the potential of using this approach to identify therapeutic targets for neuroprotection in PD. References: 1. Kordower JH, et al. Brain. 2013; 136: 2419–2431. Acknowledgements: We acknowledge funding from Science Foundation Ireland [15/CDA/3498 (GOK)] and the Irish Research Council.

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Session IV, Presentation 1 A NOVEL PARKINSON’S DISEASE MODEL: COMBINED VIRAL MEDIATED NEUROINFLAMMATION AND ΑLPHA-SYNUCLEIN AGGREGATION Laura K. Olsen1, Andrew G. Cairns2, Jörgen Ådén2, Niamh Moriarty1, Silvia Cabre1, Veronica R. Alamilla1, Fredrik Almqvist2, Eilís Dowd1, and Declan P. McKernan1. 1Discipline of Pharmacology and Therapeutics, National University of Ireland Galway, Ireland and 2Department of Chemistry, Umeå University, Sweden Background: Current animal models of Parkinson’s disease inadequately recapitulate the human condition and consequently hinder new therapy development. Clinical studies suggest that specific viral infections increase the incidence of Parkinson’s disease1. Aim: This study’s aim was to develop a novel animal model of Parkinson’s disease, combining viral mediated neuroinflammation and α-synuclein aggregation. Experimental Design: A novel synthetic molecule (FN075)2, known to promote α-synuclein fibril formation3, induced intra-neuronal α-synuclein aggregation following poly I:C (synthetic mimetic of viral dsRNA) priming. Thirty-two male Sprague Dawley rats received unilateral intra-nigral injections of poly I:C (30 µg) or saline. Two weeks later, a subsequent unilateral intra-nigral injection of FN075 (1.93 µg) or PBS+DMSO was administered. Stepping and whisker behavioural tests were conducted for seven weeks post-surgery. To assess synaptic/autophagy protein changes, in vitro cell cultures were poly I:C (20 µg/ml) primed for 24 hours before FN075 (25/50 µM) 48 hour treatment. Results: FN075 treatment produced α-synuclein aggregates in rat E14 primary TH+ neurons in vitro. In vivo, the poly I:C+FN075 combination group had significant motor deficits at five and seven weeks post-FN075. The combination treatment increased astrocytes and decreased TH+ cells in the substantia nigra at eight weeks post-FN075. In human neuroblastoma cells and rat primary ventral mesencephalic cells, poly I:C priming with FN075 altered Western Blot and Immunocytochemistry measured synaptic (synaptophysin and PSD-95) and autophagy related proteins (LC3-a/b-I/II and p62). Conclusion: Poly I:C priming with an α-synuclein aggregate promoter was able to cause significant motor deficits, along with neuroinflammation and TH cell loss. Preliminary in vitro analyses suggest synaptic dysfunction and autophagy disruption may precede neurodegeneration in this model. References: 1. Bu XL, et al. (2015) Parkinsonism Relat. Disord. 21(8): 877-881. 2. Horvath I, et al. (2012) J. Am. Chem. Soc. 134(7): 3439-3444. 3. Pedersen MN, et al. (2015) Scientific Reports. 5(10422): 1-12.

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Session IV, Presentation 2 OPTIMISATION OF A COLLAGEN-BASED DELIVERY SYSTEM FOR CELL DELIVERY TO THE BRAIN Ana L Rebelo1, Eilís Dowd2, Abhay Pandit1. 1Centre for Research in Medical Devices (CÚRAM), 2Pharmacology and Therapeutics, National University of Ireland, Galway Parkinson’s Disease (PD) is a neurodegenerative disorder primarily characterised by the death of dopaminergic neurons in the substantia nigra [1], which is related to different movement disorders [1], however currently there are only symptomatic therapies available and none of these address the specific pathophysiology of the disease [2]. Hydrogels have shown potential as a vehicle for delivery of stem cells into the brain protecting them from the host environment and increasing their viability [3]. Collagen has shown high compatibility with neural tissue [3] and is suitable for cell encapsulation. Additionally, the therapeutic potential of collagen can be further expanded by functionalising it to address a specific aspect of PD pathology. Therefore, the goal of this project is to develop and optimise a collagen-based hydrogel that will encapsulate cells to replace the dead dopaminergic neurons in the striatum. In this study, the hydrogels were optimised using cells dissociated from the E14 rat ventral mesencephalon (VM). Collagen microgels with different concentrations of collagen and 4S-StarPEG were fabricated and their physical and chemical properties studied through stability and degradation assays. It was shown that these microgels have high crosslinking efficiency and stability. Also, their biological properties were analysed, and the microgels were shown to be non-cytotoxic to Neu7 cells. Furthermore, embryonic VM rat cells were successfully loaded within the microgels. The optimised system comprised of 2 mg/ml collagen with 0.4 mM 4S-StarPEG concentration. References: [1] Moore, D. J. et al, Annual Review of Neuroscience, 28, pp. 57-87 (2005). [2] NICE Clinical Guidelines, Symptomatic Pharmac. Therapy in Parkinson’s disease, No. 35. 7, (2006). [3] Hoban, D.B. et al, Biomaterials, 34 (17). pp. 9420-9429 (2013). Acknowledgements: EU Horizon 2020 Programme (H2020-MSCA-ITN-2015) under the Marie Skłodowska-Curie Innovative Training Network and Grant Agreement No. 676408 and SFI, co-funded under the European Regional Development Fund, Grant Number 13/RC/2073.

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Session IV, Presentation 3 DESIGN OF CARBON NANOMATERIALS AS NON-VIRAL VECTORS FOR GENE THERAPY OF DISCRETE BRAIN REGIONS BY STEREOTACTIC SURGERY Sinead Savage and Kostas Kostarelos. Nanomedicine Lab, Faculty of Biology, Medicine & Health and National Graphene Institute, University of Manchester, UK The treatment of discrete brain loci is of considerable interest in various neurological disorders, such as Parkinson’s disease, epilepsy and brain tumours. Achieving gene therapy treatment in focal brain regions can offer clinical benefits, including improvements in overall functional symptoms. Viruses are the vector of choice for gene therapies of the central nervous system, however a variety of nanomaterials, such as carbon nanomaterials (graphene, carbon nanotubes) are able to allow precise localisation of the nucleic acids delivered, while preserving their in vivo stability (by enzymatic degradation) and spread of the therapy. This work looked at the spatial distribution of carbon nanomaterials administered by stereotactic surgery in specific brain locations to determine how various parameters (concentration, type of nanomaterial) determined the 3-D distribution of both the vector (nanomaterial) and a genetic payload (siRNA). Graphene oxide or carbon nanotubes were injected by stereotaxic injection into the brains of both rats and mice, either alone or bound with a fluorescently-labelled siRNA. Using sequential tissue sectioning, confocal microscopy and 3D image reconstruction, the distribution of the vector components within the brain could be determined. We can conclude that the type of nanomaterial can significantly impact the stereotactic precision in the delivery of the siRNA to brain regions to achieve different volume of the treated areas and would play a determinant role in the ultimate therapeutic effectiveness of such vector systems.

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Session IV, Presentation 4 DIRECT REPROGRAMMING OF ADULT HUMAN FIBROBLASTS: GENERATION OF DOPAMINERGIC NEURONS FOR CELL-BASED REPLACEMENT THERAPY Shelby Shrigley, Maria Pereira, Janelle Drouin-Ouellet and Malin Parmar. 1Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center, Lund University, Sweden. Cell-based replacement therapy has great potential to address the motor symptoms of Parkinson’s disease (PD), a neurodegenerative disease resulting from the progressive loss of dopaminergic cells within the nigrostriatal system. Direct neural reprogramming is a technology where a somatic cell is directly converted into an induced neuron without going through a pluripotent intermediate stage. Induced neurons (iNs) are a unique resource obviating safety concerns associated with pluripotency, as well as ethical concerns with embryonic derived cells, whilst allowing for patient specific cells or matched donors. We have previously shown that dopaminergic (DA) neuronal fate could be generated from human fetal fibroblasts using forced expression of Ascl1 and specific DA fate determinants. However, this early protocol showed low efficiency when converting adult human fibroblasts. Here we build on our reprogramming method to convert human adult fibroblasts into induced dopaminergic neurons (iDANs) with a new combination of transcription factors combined with a RE1-silencing transcription factor (REST) knock-down. High content screening analysis shows that approximately 20% of converted cells express tyrosine hydroxylase (TH) using our new reprogramming cocktail. Furthermore, there is a progressive morphological maturation from day 6 and our iDANs express both mature neuronal and dopaminergic markers. Results provide a more robust and efficient protocol for the generation of iDANs and will help to pave the way for future research assessing their potential for brain repair.

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Session IV, Presentation 5 INHIBITION OF MICRORNA-181A PROMOTES MIDBRAIN NEURONAL GROWTH THROUGH A SMAD1/5-DEPENDENT MECHANISM: IMPLICATIONS FOR PARKINSON'S DISEASE. Aideen M. Sullivan, Shane V. Hegarty and Gerard W. O’Keeffe. Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland. In Europe, 1.2 million people have Parkinson’s disease (PD) and this will double by 2030. PD is characterized by the progressive axonal degeneration of nigrostriatal dopaminergic (DA) neurons (1), however the molecular mechanisms driving this remain unclear. This is important, as identifying the causative molecular mechanisms will provide new insights into PD pathogenesis, and axonal de/regeneration. We hypothesis that microRNA (miRNA) dysregulation plays a central role in DA axonal degeneration. To test this hypothesis we carried out a bioinformatics analysis of the microRNA network that is dysregulated in PD. From this we identified miRNA-181a as a lead candidate that may regulate DA axon growth. miRNA-181a has been shown to be dysregulated in PD patients, and has been identified as a potential PD biomarker. Despite this, the role of miR-181a in mDA neurons remains unknown. Using a bioinformatics approach, we found a significant enrichment of predicted miRNA-181a target genes that were linked to functional pathways known to regulate dopaminergic axon growth (p<0.01). To investigate the functional implications of miR-181a dysregulation, we used cell culture models to show that miR-181a targets components of the bone morphogenetic protein (BMP) neurotrophic factor pathway that promotes DA axon growth. We found that inhibition of miR-181a resulted in significant increased in BMP-Smad signalling (p<0.01), and led to significant increases in Smad-dependent neurite growth in SH-SY5Y cells (p<0.01). Finally, using embryonic cultures, we demonstrated that miR-181a inhibition induced DA axonal growth, and protected DA axons against 6-OHDA-induced degeneration (p<0.01). These data suggest that miRNA-181a dysregulation in PD may contribute to DA axonal degeneration, and identifies a new therapeutic target for axonal regeneration in PD. References: 1. Kordower JH, et al. Disease duration and the integrity of the nigrostriatal system in Parkinson’s disease. Brain. 2013;136:2419–2431. Acknowledgements: We acknowledge funding from Science Foundation Ireland [Grant Number:15/CDA/3498 (GOK)].

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Session IV, Presentation 6 WHAT DOES ‘STEM CELL THERAPY’ MEAN TO PEOPLE WITH PARKINSON’S DISEASE? Chloe Turner1, Clare Nolan2, Isabelle Abbey-Vital2, Natasha Ratcliffe2, and Emma L Lane1. 1School of Pharmacy and Pharmaceutical Sciences, Cardiff University, CF10 3NB and 2Parkinson’s UK, London. Stem cell research has the potential to offer hope to many people suffering from disease or disability. Dramatic headlines in the media often erroneously portray stem cell therapy as a ‘cure’ to be ready in ‘5-10 years’. Whilst that timeline may finally be approaching realistic, is a cure really what people with Parkinson’s understand this potential therapy to be? Initially planned as Patient and Public Involvement (PPI) and subsequently developing into a more substantial set of findings, our aim was to determine whether patient concerns could potentially be readily addressed by laboratory research prior to clinical trials. This study used a mixed methods approach (questionnaire and focus groups), recruiting participants through the Parkinson’s UK Research Support Network. Qualitative data obtained from the questionnaire and focus groups were analysed thematically using inductive and deductive approaches to identify a number of themes. Quantitative data was analysed using SPSS to identify any broad correlations in the data. 528 responses to the questionnaire were received, whilst 18 people affected by Parkinson’s took part in the focus groups. Participants were of different genders and represented the spectrum of Parkinson’s from relatively early in diagnosis to living with the condition for over 11 years. Despite the caveat that the participants were self-selected from a network of people who have a specific interest in research, the number of people willing to consider stem cell therapy was very high. Concerns largely focused, as might be expected, on risks and side effects. However, expectations of the minimum outcome to be achieved from this form of therapy varied dramatically and related to the duration of disease. Often those who would be considered less likely to be candidates for the therapy (ie with more advanced disease) were most keen to take part in trials. Themes identified in the focus groups reiterated concerns around safety of the treatment, but in contrast to previous studies (Peddie et al., 2009) there was little preoccupation with the negative media surrounding earlier clinical trials. References: Peddie et al 2009, Human Reproduction 24(5) 1106-1113. Acknowledgements: This work was supported by a Parkinson’s UK Research Involvement Award and we acknowledge the valuable contribution of all the participants.

Delegate List

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Delegate List

Name Affiliation Country Email address

Dr Andrew Adler Lund University Sweden [email protected]

Ms Remsha Afzal Royal College of

Surgeons, Ireland Ireland [email protected]

Ms Verónica Alamilla National University of

Ireland Galway Ireland [email protected]

Prof Anne-Catherine Bachoud-Lévi

Mondor Biomedical Research Institute

France [email protected]

Prof Veerle Baekelandt University of Leuven Belgium [email protected]

Mr Enrico Bagnoli National University of


Ms Marcella Birtele Lund University Sweden [email protected]

Prof Anders Bjorklund Lund University Sweden [email protected]

Dr Philip Buttery Cambridge University

Hospitals UK [email protected]

Ms Silvia Cabre National University of


Prof Maeve Caldwell Trinity College Dublin Ireland [email protected]

Ms Yixi Chen University of

Edinburgh UK [email protected]

Dr Susanne Clinch Cardiff University UK [email protected]

Dr Louise Collins Cork Institute of

Technology Ireland [email protected]

Dr Ruth Concannon University College

Cork Ireland [email protected]

Prof Nicole Deglon University of Lausanne Switzerland [email protected]

Dr Eilis Dowd National University of


Dr Janelle Drouin-Ouellet Lund University Sweden [email protected]

Mr Conor Duffy Royal College of

Surgeons, Ireland Ireland [email protected]

Prof Stephen Dunnett Cardiff University UK [email protected]

Dr Charlotte Ermine The Florey Institute Australia [email protected]

Dr Orla Finucane Trinity College Dublin Ireland [email protected]

Ms Richelle Flanagan Irish Nutrition and Dietetic Institute

Ireland [email protected]

Prof Thomas Foltynie University College

London UK [email protected]

Prof Rosemary Fricker Keele University UK [email protected]

Ms Susan Gouldling Cork Institute of

Technology Ireland [email protected]

Ms Emma Green Keele University UK [email protected]

Mr Francesco Gubinelli CEA France France [email protected]

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Dr Marie-Victoire Guillot-Sestier

Trinity College Dublin Ireland [email protected]

Ms Kate Harris University of Cambridge

UK [email protected]

Ms Orla Haugh Trinity College Dublin Ireland [email protected]

Dr Andreas Heuer Lund University Sweden [email protected]

Dr Deirdre Hoban Lund University Sweden [email protected]

Dr Cameron Hunt The Florey Institute Australia [email protected]

Ms Lyndsey Isaacs Cure Parkinson's Trust UK [email protected]

Prof Lesley Jones Cardiff University UK [email protected]

Ms Rachel Kelly National University of


Dr Tilo Kunath University of

Edinburgh UK [email protected]

Prof Bob Lahue National University of


Dr Emma Lane Cardiff University UK [email protected]

Dr Mariah Lelos Cardiff University UK [email protected]

Prof Marina Lynch Trinity College Dublin Ireland [email protected]

Dr Janitha Mudannayake Lund University Sweden [email protected]

Prof Giovanna Mallucci University of Cambridge


Dr Gianvito Martino San Raffaele Hospital

Milan Italy [email protected]

Prof Nicholas Mazarakis University College


Dr Virginia Mela Rivas Trinity College Dublin Ireland [email protected]

Ms Sarah McComish Trinity College Dublin Ireland [email protected]

Dr Allison McIntosh Trinity College Dublin Ireland [email protected]

Dr Derick Mitchell IPPOSI Ireland [email protected]

Dr Kyriacos Mitrophanous Oxford Biomedica UK [email protected].

uk

Ms Niamh Moriarty National University of


Mr Alain Ndayisaba Medizinische

Universität Innsbruck Austria [email protected]

Ms Matilde Negrini Lund University Sweden [email protected]

Ms Sara Nolbrant Lund University Sweden [email protected]

Ms Justyna Okarmus University of Southern

Denmark Denmark [email protected]

Dr Gerard O'Keeffe University College


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Ms Laura Olsen National University of


Dr Clare Parish The Florey Institute Australia [email protected]

Dr Gesine Paul Lund University Sweden [email protected]

Dr Anselme Perrier INSERM France [email protected]

Ms Anna-Luise Platz Medical University

Innsbruck Austria [email protected]

Ms Ana Lúcia Rebelo National University of


Dr Claire Rice University of Bristol UK [email protected]

Dr Sarah-Jane Richards Ormer Ltd. UK [email protected]

Prof Harry Robertson Dalhousie University Canada [email protected]

Ms Carol Rogan Dementia and

Neurodegeneration Network Ireland

Ireland [email protected]

Dr Marina Romero-Ramos Aarhus University Denmark [email protected]

Prof Anne Rosser Cardiff University UK [email protected]

Dr Ana Rubio Araiz Trinity College Dublin Ireland [email protected]

Dr Astrid Sasse Trinity College Dublin Ireland [email protected]

Dr Sinead Savage University of Manchester


Ms Sissel Ida Schmidt University of Southern

Denmark Denmark [email protected]

Ms Shelby Shrigley Lund University Sweden [email protected]

Prof Maria Spillantini University of Cambridge


Dr Simon Stott University of Cambridge


Prod Aideen Sullivan University College


Prof Sarah Tabrizi University College


Dr Lachlan Thompson The Florey Institute Australia [email protected]

Prof Leslie Thompson University of

California, Irvine United States

[email protected]

Prof Gregor Wenning Medizinische

Universität Innsbruck Austria [email protected]

Dr Alan Whone University of Bristol UK [email protected]

Prof Hans Rudolf Widmer University of Bern Switzerland [email protected]

Dr Richard Wyse Cure Parkinson's Trust UK [email protected]

Dr Emma Yhnell Cardiff University UK [email protected]

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ntar2017 - nectar€¦ · nectar 2014 in galway. after the conference, excerpts from toms...

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