mnd research in ireland
TRANSCRIPT
MND RESEARCH IN IRELAND
Time for Optimism
Orla Hardiman BSc MD FRCPI FTCD MRIAProfessor of NeurologyTrinity College Dublin
IRELAND IS A LEADING INTERNATIONAL RESEARCH
HUB IN MND
TRINITY COLLEGE DUBLIN • 50+ brilliant young researchers• World class science• 20+ PhDs in the past 10 years• Innovative cross-disciplinary projects
– Neurological evaluation– Neuropsychology– Epidemiology– Genetics– Neural Engineering– Mathematics– Statistics– ICT Platform technology – Health Services Research – Burden & Health Economic outcome– New Drug Development – Clinical Trials
Mark Heverin Research Manager
OBJECTIVE
To understand the causes of MND to the extent that we can develop new and
more effective treatments .
WE INVEST IN TALENT AND EXCELLENCE
Miriam Galvin, Assoc Professor in Research Methods
Niall Pender, Assoc Professor in Neuropsychology
Peter Bede, Professor in Brain Imaging
Russell McLaughlin Ussher Assistant Professor,ALS/MND Genomics
Bahman Nasserelsoslami, Fr.Tony Coote Assistant Professor in ALS/MND
Dara Meldrum, Assoc Professor in Clinical Measurement, Deirdre Murray, Assist. Prof in Clinical Measurement
SOME OF OUR WORK… • First to provide a sustainable population based register in ALS &ALS/FTD (27 years)• Acknowledged leadership in population based Register design• First to show that ancestral origin is an important risk in ALS• First to show survival benefit of multidisciplinary clinics • First to show using population data that heritability is high in ALS (0.53)• First to fully describe the population based relationship between ALS and Dementia• First to demonstrate expanded phenotype in C9orf72 related disease • Found important new genes in ALS/MND ANG, NEK1,• Discovered and proved an important biological link between ALS/MND and
Schizophrenia using epidemiology and genomics• Demonstrated new data driven patient subgroups using of brain imaging and signal
analysis• First to Deconstruct measurement scales showing-major floor & ceiling effects • First to validate ECAS & to generate & validate a new ALS Specific behavioural scale • Development of clinical meaningfulness attributes • Development of detailed Caregiver Burden Data• New system for using EEG to measure change in brain function in MND
CURRENT STATE OF THE ART IN
IRISH MND RESEARCH
ALS: A Gene-environment Interaction(in 6 steps)
Hardiman & Al-Chalabi Nat Rev Neurol 2013Al-Chalabi et al Lancet Neurol 2015Chio et al Neurology 2018
3-5 additional events
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Heritability overall population
Overall Daughter-mother Son-mother Daughter-father Son-father
Heritability Estimates using the Irish ALS/MND Register
Genetics account for approximately 50% of the risk of developing MND (at population level)
JAMA Neurol. 2019 Nov 1;76(11):1367-1374.
THE HUNT FOR GENES
GENES ASSOCIATED WITH ALS
Gregory, J.M et al . Curr Genet Med Rep 8, 121–131 (2020)
30 GENES OF MAJOR EFFECT
Not All Gene “mutations” cause disease!
alsftd.tcd.ie Mark Doherty & Russell McLaughlin
CAUSES OF MND: CURRENT CONCEPTS
UNDERSTANDING THE CAUSE OF DISEASE CAN INFORM NEW DRUG
DEVELOPMENT
SOD1 TRANSGENIC ANIMAL MODEL
– Does the drug work?– Is the drug toxic?
LESSONS FROM THE SOD1 MOUSE
MANY GOOD DRUGS FAIL IN THE “VALLEY OF DEATH”
Mouse Problems
• Animal models useful but limited…
– Anatomy differs– Genetic background important: “strain effect”– Gender Differences– Effects of multiple copies of an inserted human
gene
– (DIFFERENT PATHOLOGY..)
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ALS mSOD1 Transgenic Mice
Human MND
Of Mice and Men: Homogeneity versus Disease Onset and Progression
THE TRANSLATION PROCESS ISN’T WORKING….
MMD:A COMPLEX HUMAN DISEASE
SPECTRUM
“Pure”ALS
ALS and Dementia
15%
ALS and Behavioural Impairment
HUMAN MNDNOT JUST MOTOR NEURONS
ALS and Cognitive Impairment
Up to 35%Up to 70%
No abnormality detected
47%
Executive Dysfunction21%
Non-executive Cognitive Impairment
14%
ALS-FTD14%
Comorbid Alzhemier's Disease 2%
Neurology Clinical Practice 2020
J Neurol Neurosurg Psychiatry. 2012 Jan;83(1):102-8.
Behaviour Classifications
Factor Loading
Superordinate Classification of
Dysfunction
Cognitive/Behavioural Dysfunction
1 Initiation (Apathy) Loss of interest; inability to plan; impulsiveness; decreased sex drive; lack of appropriate embarrassment.
2 Adherence to social norms
Emotional changes; social disinhibition; social seeking.
3 Social Engagement Social withdrawal; distractibility; cognitive rigidity.
4 Interpersonal Engagement
Aggressiveness; irritability; Increased lability; hypersensitivity to stimuli.
5 Self-regulation Reduced concern for hygiene; change in food preferences; new onset repetitious/obsessive behaviour.
Elamin M et a; Identifying behavioural changes in ALS: Validation of the Beaumont Behavioural Inventory (BBI). Amyotroph Lateral Scler Frontotemporal Degener. 2017 Feb;18(1-2):68-73
MND AND FRONTOTEMPORAL DEMENTIA ARE PART OF A SPECTRUM
MND IS MORE THAN ONE CONDITION
PRECISION MEDICINE
PRECISION MEDICINEPrecision Medicine refers to the tailoring of medical treatment to the individual characteristics of each patient…..It relates to the ability to classify individuals into subpopulations that differ in their susceptibility to a particular disease, in the biology and/or prognosis of those diseases they may develop, or in their response to a specific treatment.
ARE THERE KNOWN ENVIRONMENTAL RISKS?
EUROMOTOR studyLAENALS studyMetALS study
Environmental “exposures” very are hard to detect
We need very big numbers, and combinations of different types of data
WHAT CAN WE LEARN FROM “FAMILIAL” MND IN IRELAND?
KNOWN GENES
• C9orf72 accounts for 30-50% of known “familial” ALS in European populations
In Ireland up to 20% of people with ALS have another family member
with MND or FTD
50% of these kindreds carry the C9orf72 repeat expansion
…WHAT ELSE ARE WE MISSING… ?
ALS
Frontotemporal dementia
Psychosis
Impulse dyscontrol
Autism
Bipolar disorder
Other Related Conditions in some MND Families
OCD
O’Brien et al, JAMA Neurol 2017 Dec 1;74(12):1425-1430.
Alcohol overuse
“SUPERFAMILIES”
Summary So Far..
• Studying family members of those with MND has shown us that there is a link between some forms of MND and some psychological (and psychiatric) traits
• This link is probably related to how different brain networks operate
• Understanding these links will help us to better understand MND and to find better treatments
CONCEPTUAL SHIFT:
MND IS A HUMAN SYNDROME THAT IS BEST UNDERSTOOD AS ADISORDER OF BRAIN NETWORKS
BRAIN IMAGING
CAN RELIABLY DEMONSTRATE EXTRA-MOTOR INVOLVEMENT IN REGIONS THAT PREDICT COGNITIVE /BEHAVIOURAL CHANGE
MRI CHANGES IN MND
APPLIED BRAIN WAVE ANALYSIS (EEG)
Finding different patterns of brain network disruption in MND:
Can help to find subgroups and to decide if a drug is working
Human Brain Mapping 2019
Characteristic patterned changes of brain wave activity identifies brain network disruption
Trinity College Dublin, The University of Dublin University Medical Centre Utrecht
PATTERNED NETWORK CHANGES IDENTIFY DISEASE SUBGROUPS
Clinical profiles
Dukic et al, Brain 2021 (In press)
ACTIVATING DIFFERENT BRAIN NETWORK PATTERNS
MISMATCH NEGATIVITY (MMN) STUDIES
Trinity College Dublin, The University of Dublin
Harnessing source localisation to study ALS
Iyer et al., 2017
The Mismatch Negativity Response
Involuntary attention switching Mismatch negativity wave
Trinity College Dublin, The University of Dublin
THE SUSTAINED ATTENTION TO RESPONSE TASK (SART)
Response inhibition upon number 3
3
Robertson et al., 1997
• Motor and cognitive task
• Behavioural results alone insensitive to early ALSci
• EEG measures can determine cognitive/motor subdomains and regions affected
IRISH MND RESEARCH INTHE
EUROPEAN CONTEXT
Treatment Research Initiative to Cure ALS
The TRICALS consortium
UKNetherlandsIrelandItalySwedenFranceSpainBelgium
TRICALS: a consortium that delivers
• ENCALS• Generating international standards & biobanks
– SOPHIA Biomarkers– EuroMotor Pan-European database, -omics– STRENGTH Genetics, lifestyle & environment– NETCALS Patient cohorts– BRAIN-MEND Disease clustering– ALS-CarE Patient care journeys
• Project MinE• Progeny: harmonized, shared database
MISSION
THE RIGHT DRUG, FOR THE RIGHT
PATIENT, IN THE RIGHT DOSE, AT THE
RIGHT TIME
FINDING MORE GENES
Capitalising on Project Mine
Unites researchers and fundraisers
18+ Million raised in 17 countries
10,605 genomes sequenced
Expanding globalcollaboration
Translate genetics to clinical studies
OBJECTIVES
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1. Combine different European datasets to reveal subgroups of patients
2. Develop and implement single set of biomarkers to measure disease progression
3. Improve clinical trial design to best test noveltreatments in distinct subgroups
4. Develop a pan-European platform to collect data and coordinate clinical studies
5. Develop (patient reported) outcome measures to assess cost-effectiveness of new therapeutics
Highway to therapy
REALTIME DATA UPLOADS for TRIAL READINESS
A pan-European Electronic Patient Record
BETTER ACADEMIC/INDUST
RYCOLLABORATION
REAL WORLDDATA ANALYTICS "BETTER TRIALS " BETTER CLINICAL
OUTCOMESEDUCATION(BIG DATA)
HEALTHECONOMICS
LARGEPATIENT COHORTS
CLUSTERINGOF PATIENTS
NOVEL BIOMARKERS(IMAGING/ SIGNAL
ANALYSIS)
GENE BASED THERAPIES CAREGIVER DATA SURVIVORSHIP
ANALYSES
REAL WORLD DATA CLINICALMEANINGFULNESS
NOVELBIO-MARKERS
(WET)
NOVELOUTCOME MEASURES
BETTER CAREPATHWAYS
NOVELTELEMEDICINE
CLINICALEVALUATION
(PHENOTYPING)
DIGITAL OUTCOMEMEASURES COGNITION EXISTING "WET"
BIO-MARKERSDRUG TREATMENTS
REMOTE MONITORING
IMAGING(MRI)
NEUROELECTRIC SIGNAL
ANALYSIS
PATIENTPORTAL
CAREGIVERPORTAL ENABLING
DEVICES
PRIARY LATERAL SCLEROSIS
SOCIETAL BENEFITS
PRECISION MEDICINE CLINICAL TRIALS
MACHINE LEARNING
DATA ANALYTICSMULTIMODAL
PLATFORMDATAPATIENT CHARACTERISTICS
DATA MANAGEMENT
GOVERNANCE
DISEASE FOCUS
AMYOTROPHIC LATERAL SCLEROSIS
PROGRESSIVE MUSCULAR ATROPHY
PROGRESSIVE BULBAR PALSY
GENOMICS
BEHAVIOURAL VARIANT FTD
PRECISION ALS
WHAT ABOUT CLINICAL TRIALS?
MND TRIALS: The Past
• > 40 negative trials• Animal-based approach has not been
successful • Effective treatments likely to be in subgroups
of patients• Better biomarkers required • Trial design and outcome measures need to
be refined
Over 20 compounds now in late pre-clinical phase
NEW “DESIGNER” TREATMENTS
• Based on genetics– Anti-sense oligonucleotides
•SOD1•C9orf72 repeat expansion
MORE NEW TRIALS (Starting this year)
• MERIDIAN • ADORE • COURAGE • PHOENIX • LIGHTHOUSE• MAGNET
TAKING CARE OF ALL THOSE WITH MND
The Importance of a National Multidisciplinary Clinic
IMPROVING THE PATIENT PATHWAY
PATIENT centricCAREGIVER centric
• Understanding experiences of the illness beyond the disease pathology
• Patients and caregivers as collaborative partners• Attribution of clinical meaningfulness• Incorporation of patient reported outcomes• Appropriate applications of user-friendly
technology
Private & confidential
UNDERSTANDING THE NEEDS OF CAREGIVERS
Partnering with the Patient and Caregiver:
A Novel approach to deliver clinically meaningful benefits
Integrating Digital Healthcare Technology to Reduce Burden of
Evalution
01/10/2021 © The University of Sheffield
TELEMEDICINE IN MND
CONCLUSIONS
• Irish MND research is at the cutting edge and has made many important discoveries
• The Irish MND Research team works closely with all major European centres as part of the TRICALS Consortium : Together we will find new and more effective treatments
• The Research team is grateful to all Irish people with MND families for their generosity in helping us to understand this condition & to find new treatments
• The Research team is grateful to the IMNDA for their unwavering support over the past 30 years
Team Applied ClinicalBernie CorrAisling O’ReillyOlivia GroganTrion MannermanDr.Deirdre MurrayDr.Dara MeldrumMairead CampbellLesley DoyleKitty McElligott
Imaging & EEGDr.Peter BedeDr.Bahman Nasseroleslami Dr.Róisín McMackinDr.Eoghan FinneganDr.Amina CoffeyStefan DukicSaroj Bista
NeuropsychologyDr.Niall PenderDr.Marta PintoDr.Marwa ElaminEmmet Costello
EpidemiologyDr.Marie RyanDr.James RooneyColm Peelo
Genetics Prof Dan BradleyDr.Russell McLaughlinDr. Kevin KennaDr. Ross ByrneMark Doherty
Academic NeurologySara Batsukh
Health ServicesDr. Miriam GalvinDr.Sinead Maguire
EMG & BiomarkersDr.Amina Coffey Dr.Lara McManus
Clinical TrialsLiz FogartyDr. Sinead MaguireDr.Amina CoffeyDr.Sarah Darcy
Research ManagerMark Heverin
Laboratory/NeuropharmDr. Julie Kelly
RESEARCH FUNDING