ucl-birkbeck mrc dtp experimental and personalised

UCL-Birkbeck MRC DTP

Experimental and Personalised Medicine

PROJECT BOOKLET 2021/22

UCL Birkbeck MRC DTP 2021/22

Alastair O'Brien

Position: Professor of Experimental Hepatology Location: Institute of Liver & Digestive Health, Royal Free Email contact: [email protected] Theme: Experimental and Personalised Medicine

Research overview (50 words or less)

My group uses a combination of laboratory experimental medicine models and large-scale clinical trials to improve treatment of bacterial infection in patients with advanced liver cirrhosis, which is one of their most common causes of hospitalisation and death.

Rotation project:

Investigating novel therapies to prevent infection in patients with advanced liver cirrhosis: Liver cirrhosis is a common cause of death, in which patients develop multiple bacterial infections because of a dysfunctional immune response, leading to sepsis. No treatments to improve immune dysfunction exist and my research programme aims to change this. Data using samples from our recent large, randomized trial of albumin infusions showed elevated levels of the lipid mediator Leukotriene B4 (LTB4) was associated with improved 3-month survival in female patients. Further work suggests this relates to its neutrophil chemoattractant abilities. We showed that, although activated, cirrhotic patients’ neutrophils have reduced phagocytosis and hypothesise that patients with high LTB4 levels have increased numbers of neutrophils transmigrating to infection sites, overcoming the individual cells poor function, thereby reducing rates of sepsis. Testosterone inhibits LTB4 production leading to higher levels in women, which may account for their improved outcomes in cirrhosis. This project will combine laboratory models of neutrophil function linked to clinical outcome data using samples from our unique >800-patient trial to determine whether increased plasma LTB4 improves the neutrophil response to infection with an overall aim to develop a precision medicine approach to immune restorative therapy for patients with cirrhosis.

Relevant publications

1. A Randomized Trial of Albumin Infusions in Hospitalized Patients with Cirrhosis. China L, …. & O'Brien A; ATTIRE Trial Investigators. N Engl J Med. 2021 Mar 4;384(9):808-817. doi: 10.1056/NEJMoa2022166.

2. Immune Regulatory Mediators in Plasma from Patients With Acute Decompensation Are Associated With 3-Month Mortality. Becares N… & O'Brien A. Clin Gastroenterol Hepatol. 2020 May;18(5):1207-1215.e6. doi:10.1016/j.cgh. 2019.08.036. Epub 2019 Aug 22.

3. Immunosuppression in acutely decompensated cirrhosis is mediated by prostaglandin E2. O'Brien AJ, et al. Nat Med. 2014 May;20(5):518-23. doi: 10.1038/nm.3516. Epub 2014 Apr 13.

mailto:[email protected]


Alessia Cavazza

Position: Lecturer in Gene Therapy Location: GOSICH Research & Teaching Department Email contact: [email protected] Theme: Experimental and personalised medicine


Cavazza’s lab is dedicated to generating gene therapies for primary immunodeficiencies in children, many of whom cannot be cured by any existing therapies. Our research aims to cure these children by editing their own stem cells and reimplanting them, allowing them to develop healthy immune systems.

Rotation project

Development of a CRISPR/Cas9 gene editing platform to correct Severe Combined Immunodeficiency caused by mutations in the IL7RA gene

IL7R Severe combined immunodeficiency (SCID) is a genetic disorder caused by IL7R deficiency which leads to absence of T lymphocytes resulting in profound failure of the immune response, with severe and opportunistic infections leading to fatal outcome. While hematopoietic stem cell (HSC) transplantation is curative for all forms of SCID, incomplete immune reconstitution and toxicities can cause significant morbidities, meaning that alternative approaches are desirable. Gene therapy applied to IL7R SCID has shown that constitutive and unregulated expression of the gene predisposes to leukemia. Genome editing represents a promising alternative as it could correct the endogenous IL7R locus while avoiding issues of unregulated transgene expression. The goal of this project is to develop CRISPR/Cas9-based genome editing to functionally correct mutations in the IL7R genes in HSCs derived from SCID patients. Our preliminary results have shown that by delivering our optimized CRISPR/Cas9 reagents together with an AAV6 donor template we are able to efficiently knock-in a reporter cassette into the IL7R locus in up to 50% of HSCs. We now aim to move forward and restore IL7R expression in IL7R deficient cells from SCID patients, to establish a viable gene editing-based therapeutic approach to treat IL7R SCID.


1. Rai R., Thrasher AJ., Cavazza A. (2020). Gene editing for the treatment of Primary Immunodeficiencies. HUMAN GENE THERAPY, 2020 https://doi.org/10.1089/hum.2020.185

2. Rai, R., Romito, M., Rivers, E., Turchiano, G., Blattner, G., Vetharoy, W., ...Cavazza, A. (2020). Targeted gene correction of human hematopoietic stem cells for the treatment of Wiskott - Aldrich Syndrome. NATURE COMMUNICATIONS, 11 (1), doi:10.1038/s41467-020-17626-2

3. Jiang Q, Li WQ, Aiello FB, et al. Retroviral transduction of IL7Ralpha into IL7Ralpha-/- bone marrow progenitors: correction of lymphoid deficiency and induction of neutrophilia. Gene Ther 2005;12:1761-1768



Dr Alvena Kureshi Position: Lecturer in Bioengineering Location: UCL Division of Surgery & Interventional Science, Charles Bell House, Bloomsbury campus

Email contact: [email protected] Theme: Experimental and Personalised Medicine (EPM)


Bioengineering 3D in vitro tissue models to study the biology of hernias

My research interests are focused on engineering 3D biomimetic collagen tissue models that mimic the architecture of tissues. I am currently focusing on understanding the biology of ventral hernias and working towards the development of a novel tissue engineered surgical mesh.

Rotation project Hernias occur when an organ protrudes out of the cavity it is normally contained within. The exact causes of this condition are unknown, but it often occurs after events where there is an increase in intra-abdominal pressure such as heavy weight lifting, excessive coughing or pregnancy. The rectus sheath is the main tissue layer in the abdominal wall that is affected in ventral hernias. This tissue layer is usually reinforced with surgical meshes during hernia repair. However, the properties of these surgical meshes do not resemble the tissue properties of the rectus sheath and this may be leading to complications such as pain, adhesions and recurrence experienced post-operatively by patients. In this project, you will engineer 3D in vitro tissue models to recapitulate the structure of the rectus sheath and examine closely how cells respond to different structural cues and how this may affect their function.

Rotation project aims: 1. Bioengineer and characterize a 3D in vitro collagen tissue model of the rectus sheath

Long term (PhD project) aims: 2. Utilise (aligned vs unaligned) tissue model to examine human healthy and hernia fibroblast-ECM responses 3. Assess changes in structural and mechanical properties 4. Compare properties under normal and hernia physiological loading

Relevant publications Grillo A., Hyder Z., Mudera V., Kureshi A. (2021) In vitro characterisation of low-cost synthetic meshes intended for hernia repair in the UK. Hernia. Apr 2. doi: 10.1007/s10029-021-02401-z. Epub ahead of print. PMID: 33797680.

Whitehead-Clarke T., Karanjia R., Banks J., Beynon V., Parker S., Sanders D., Mudera V., Windsor A., Kureshi

A. (2021) The experimental methodology and comparators used for in vivo hernia mesh testing; a ten year scoping review. Hernia. Published Online First 12 January 2021 https://doi.org/10.1007/s10029-020-02360-x

Skopec M., Grillo A., Kureshi A., Bhatti Y., Harris M. (2020) Double standards in healthcare innovations – the case of mosquito net mesh for hernia repair. BMJ Innovations. Published Online First: 14 December 2020. doi: 10.1136/bmjinnov-2020-000535

Player D. J., Kureshi A., Mudera V. (2019) Engineering of Collagen as a Functional Biomaterial. In Comprehensive Biotechnology, Vol. 5, Moo-Young, M., Ed., Elsevier: Pergamon pp 442–456.

Mukhey D., Phillips J., Daniels. J.T, Kureshi A. K. (2017) Controlling human corneal stromal cell contraction to mediate rapid cell and matrix organization of real architecture for 3-dimensional tissue equivalents. Acta Biomaterialia. 67:229-237. doi: 10.1016/j.actbio.2017.11.047.


https://doi.org/10.1007/s10029-020-02360-x


ANISUR RAHMAN

Position: Professor of Rheumatology Location: Rayne Institute, Division of Medicine Email contact: [email protected] Theme: Experimental and Personalised Medicine


My group studies pathogenesis, clinical outcomes and development of potential new therapies for autoimmune rheumatic diseases, particularly systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). By identifying the key antigen/antibody interactions that lead to clinical effects in these diseases we aim to develop new forms of therapy.

Rotation project Systemic lupus erythematosus (SLE) is an autoimmune disease with a prevalence of 1 in 1000 in the UK. SLE is particularly dangerous when it causes inflammation of the kidney - lupus nephritis (LN). LN can cause renal failure or death. There are two major forms of LN that are distinguishable in biopsies; proliferative LN (PLN) and membranous LN (MLN) We have recently published a study of 187 patients with LN followed for up to 42 years (mean 12 years) of whom 21% developed kidney failure. Antibodies to double-stranded DNA are believed to be critical in the pathogenesis of PLN, However, we have shown that neither anti-dsDNA nor antibodies to antigens known to be involved in other forms of kidney disease are pathogenic in MLN. This project aims to identify antibodies to one or more currently undetermined renal antigens that play the key role in the pathogenesis of MLN.

1) Purified IgG from patients with PLN, MLN and healthy controls will be attached to Protein G beads and these beads exposed to lysates of cultured human podocytes and separately to glomerular lysates from healthy human kidneys. Western blotting will be used to identify and separate proteins within the lysates that bind only MLN IgG. These proteins will be identified by mass spectrometry.

2) We will use laser microdissection of glomeruli from healthy human kidney tissue and from biopsies of patients with MLN or PLN to investigate whether the antigens identified in point 1) above are expressed in MLN tissue.

3) We will use immunohistochemistry to investigate the pattern of expression of these antigens in renal biopsies from patients with MLN, PLN and healthy human kidney tissue.


• Rahman A and Isenberg DA. Systemic lupus erythematosus. New England Journal of Medicine 358; 929-39 (2008)

• Hanly, J.G., et al., The frequency and outcome of lupus nephritis: results from an international inception cohort study. Rheumatology (Oxford), 2016. 55(2): p. 252-62.

• Farinha, F., et al., Outcomes of membranous and proliferative lupus nephritis - analysis of a single-centre cohort with more than 30 years of follow-up. Rheumatology (Oxford),

2020. 59(11): p. 3314-3323.



Christiana Ruhrberg

Position: Professor Location: UCL Institute of Ophthalmology Email contact: [email protected] Theme: Experimental Medicine


Blood vessels distribute oxygen, nutrients and immune cells. Accordingly, dysfunctional vasculature contributes to heart and lung disease, blindness and thrombosis. Dysfunctional vasculature first arises during foetal development (congenital disease) or subsequently by infection or lifestyle (acquired disease). The Ruhrberg lab studies the molecular and cellular mechanisms of vascular disease.

Rotation project

To understand the origins of cardiovascular disease and underpin the rational design of pro-angiogenic therapies for ischemic diseases, the student will contribute to research seeking to define the molecular and cellular mechanisms of tissue vascularisation in health and disease.

The project will focus the endothelial cells that form the inner lining of all blood vessels and which respond to growth factor and extracellular matrix signals for tissue vascularisation. We have identified several endothelial signalling pathways that regulate lung and brain vascularisation but are perturbed in disease, including, for example, in eye disease or Downs Syndrome.

The student can choose to investigate these pathways in human and/or animal endothelial cells and tissues, choosing from a range of techniques, including cutting edge transcriptomic biochemical, cell biological or imaging methods.

Relevant publications (5 selected publications)

• Fantin, A., et al. and Ruhrberg, C (2021). KIT is required for fetal liver hematopoiesis. Frontiers Cell & Developmental Biology (in press).

• Brash, J.B., Denti, L., Ruhrberg, C. *, Bucher, F. * (2019). VEGF188 promotes corneal re- innervation after injury. JCI Insight 4(21); pii: 130979.

• Plein, A., et al. and Ruhrberg, C. (2018). Erythro-myeloid progenitors contribute endothelial cells to developing vasculature. Nature, 562(7726):223-228.

➢ News & Views: A dual origin for blood vessels (2018). Nature 562: 195-197. ➢ Faculty of 1000: very good and good; https://facultyopinions.com/prime/734075201

• Raimondi, C., Fantin A., Lampropoulou, A., Denti, L., Chikh, A. and Ruhrberg, C. (2014). Imatinib inhibits VEGF-independent angiogenesis by targeting NRP1-dependent ABL1 activation in endothelial cells. Journal of Experimental Medicine 211(6): 1167-1183

➢ Faculty of 1000: recommended read; http://f1000.com/prime/718419118

• Fantin, A., et al. and Ruhrberg, C. (2010). Tissue macrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction. Blood 116 (5):829-840. Cover image

➢ New & Views: Bridges that guide and unite (2010). Nature 465: 697-699. ➢ Faculty of 1000 Biology: must read http://www.f1000biology.com/article/id/116078


http://f1000.com/prime/718419118

http://www.f1000biology.com/article/id/116078


Prof Claudia Mauri

Position: Professor of Immunology Location: Pears Building, Institute of Immunity & Transplantation Email contact: [email protected]

Theme: Experimental and Personalised Medicine (EPM)


Research in the Mauri lab focuses on delineating the cellular and molecular mechanisms controlling immune-regulation in health and how these pathways are dysregulated in cancer and autoimmunity. In particular, my lab focusses now of how changes in diet affect the microbiota and the effect of microbiota derived signals have on regulatory B cell function. More recently we have focussed on the metabolic aspect regulating B cells function in autoimmunity and in cancer.

Rotation project IL-10-producing regulatory B-cells (Bregs) reside in the intestine, where it has been suggested that they contribute to the maintenance of gut-homeostasis1,2. Bregs differentiate in response to factors produced by gut-bacteria (e.g. butyrate) and intestinal epithelial-cells (IEC) (e.g. serotonin)3. In arthritis we have recently shown that there is inflammation in the gut, that there is a loss of IEC integrity and IL-10R expression accompanied by gut leakiness, as well as a significant loss of Breg- promoting butyrate and serotonin3,4. Intestinal barrier damage is a characteristic of several immune related diseases including some type of cancers. The degree to which specialised intestinal-Bregs contribute to gut homeostasis in health, and how much of this protection is lost in disease (for example in patients with autoimmunity that does not involves the gut or in patients for example with renal or breast cancer), is unknown. We suggest that the crosstalk between specialised epithelial cells and Bregs is crucial to both intestinal and peripheral tolerance, and that restoring this interaction in cancer or in autoimmunity would reduce both gut and systemic inflammation. We therefore suggest that by understanding better the interplay between the gut-bacteria, specialised epithelial cells and cells of the immune system will permit us to identify novel therapeutic target to treat systemic immune-related disorders. To address this hypothesis, we will define the specific adaptations of Bregs to the intestine and how IECs support their function in murine models of arthritis and translate the findings in samples from patients and healthy controls. The student will be joining an interdisciplinary team of collaborators (including bioinformatician that provide daily help for the analysis of data) and to address our hypothesis will use a combination of single cell RNA seq, flow cytometry and microscopy.


1. Oka, A. et al. Role of regulatory B cells in chronic intestinal inflammation: association with pathogenesis of Crohn's disease. Inflamm Bowel Dis 20, 315-328 (2014).

2. Rosser, E.C. et al. Microbiota-Derived Metabolites Suppress Arthritis by Amplifying Aryl- Hydrocarbon Receptor Activation in Regulatory B Cells. Cell Metab 31, 837-851 e810 (2020).

3. Rosser, E.C and Mauri C. The emerging field of regulatory B cell immunometabolism. Cell Metabolism. 2021 Jun 1;33(6):1088-1097.

4. Matei et al., Intestinal barrier dysfunction plays an integral role in arthritis pathology and can be targeted to ameliorate disease. Med (2021). https://doi.org/10.1016/j.medj.2021.04.013



David Abraham/Jan Willem Taanman

Position: Inflammation/Neuroscience Location: UCL Royal Free Campus Email contact: [email protected] Theme: Experimental and Personalised Medicine (EPM)

Research overview (50 words or less) Exploring inflammatory networks and the phenotypic switching of fibroblast cell senescence. Senescence or biological ageing is associated with a profound reprogramming of cellular function involving cell cycle arrest, reduction of the internal clock (shortening of telomeres), generation of reactive oxygen species, altered mitochondrial metabolism and acquisition of a senescence-associated secretory phenotype (SASP) characterised by the constitutive secretion of cytokines and growth factors. There is growing evidence that in age-related chronic inflammatory diseases, characterised by prolonged inflammation (over many years) has a major impact on cell senescence and the progression of inflammatory lesions leading to tissue scarring and fibrosis.

Rotation project The aim of this rotation is to explore the expression of fibroblast cellular senescence in a chronic inflammatory autoimmune disease by examining the cell cycle, mitochondrial biology and the role of SASP inflammatory factors (IL-6, SDF1) on fibroblast phenotype. Rotation project will include: 1. Examination of senescence markers (e.g. p16/p21) in chronic inflammatory lesions. This will be

performed using immunohistochemistry and tissue sections with fluorescence probes. 2. Investigation of the mitochondrial metabolism of inflammatory fibroblasts. Here we will use the

Seahorse respirometery and the ‘Mito’ plates to explore mitochondrial function and changes in functional activity upon senescence.

3. Determination of the inflammatory fibroblast SASP by measuring secretomes. This part of the rotation will ue the multi-plex Luminex system to assess ~ 40 cytokines/chemokines simultaneously.

4. The impact of SASP on fibroblast behaviour by measuring differentiation and scar tissue. Primary fibroblast will be culture in vitro and their production of ECM (collagen type I and fibronectin) will be measured along with heir expression of myofibroblast markers (alpha-SAM, smoothelin and Sm22). Understanding the role of fibroblast senescence in age-related inflammatory diseases will lead to the targeted use of senolytic drugs aiding the development of new treatment avenue.

Relevant publications: 1. Mitochondria as target to inhibit proliferation and induce apoptosis of cancer cells: the effects of

doxycycline and gemcitabine.Dijk SN, Protasoni M, Elpidorou M, Kroon AM, Taanman JW.Sci Rep. 2020 Mar 9;10(1):4363. doi: 10.1038/s41598-020-61381-9.

2. Myofibroblast fate plasticity in tissue repair and fibrosis: de-activation, apoptosis, senescence and reprogramming. Merkt W, Zhou Y, Han H, Lagares D. Wound Repair Regen. 2021 Jun 11. doi: 10.1111/wrr.12952

3. Oxidative stress-induced senescence mediates inflammatory and fibrotic phenotypes in fibroblasts from systemic sclerosis patients. Mancini OK, et al Rheumatology (Oxford). 2021 Jun 11:keab477. doi: 10.1093/rheumatology/keab477

4. Insights into myofibroblasts and their activation in scleroderma: opportunities for therapy? Gyftaki- Venieri DA, Abraham DJ, Ponticos M.Curr Opin Rheumatol. 2018 Nov;30(6):581-587

5. Frontiers of Antifibrotic Therapy in Systemic Sclerosis. Distler JH, Feghali-Bostwick C, Soare A, Asano Y, Distler O, Abraham DJ. Arthritis Rheumatol. 2017 Feb;69(2):257-267


https://pubmed.ncbi.nlm.nih.gov/32152409/









David Abraham/Jan Willem Taanman

Position: Inflammation/Neuroscience Location: UCL Royal Free Campus Email contact: [email protected] Theme: Experimental and Personalised Medicine (EPM)


Metabolic and Biosynthetic Profiling in Fibrosis. Our preliminary studies have revealed that fibrotic cells appear to exhibit altered glycolysis and oxidative phosphorylation implicating energy metabolism as key processes underlying the development of fibrosis. We wish to build upon and ultimately exploit this knowledge and develop methods to interfere or pharmacologically inhibit these pathological pathways. Modulating or interfering with specific metabolic pathways represents a subtle way to alter differentiation and functional activities for therapeutic advantage.

Rotation project Objectives: The overall goal of this project is to investigate the nature of the biochemical switching and metabolic reprogramming in cell differentiation and explore the link between metabolic switching and to the development of myofibroblasts, altered secretomes and scar formation in scleroderma in order to develop therapeutic strategies that target the disrupted and normalize cell metabolism. The four key aims are to: 1. Fully dissecting glycolysis and oxidative phosphorylation (OXPHOS) to investigate the

molecular basis of metabolic switching in scleroderma fibroblasts and control fibroblasts upon growth factor treatment. Here we will use the Seahorse Flux system to assess glycolysis and OXPHOS in the absence and presence of defined glycolytic and metabolic inhibitors including FAO inhibitors.

2. Investigate the mitochondrial morphology and expression of proteins that control morphology and function to gain insights into the cause of mitochondrial hyperfusion in patient fibroblasts. In these studies the student will examine the molecular basis for mitochondrial fission vs fusion and mitophagy using vital dyes and mitochondrial ubiquitination.

Expected outcomes: This study will reveal fundamental aspects of energy metabolism and mitochondrial function in fibrosis and show how energy production is regulated and the mechanisms that cells use to choose a particular energy generation route. In addition, by analysing metabolic programs in both fibroblasts and myofibroblasts the studies will provide an insight into how different metabolic strategies influence cellular behaviour and the key differences in scleroderma. This work will also yield important insights into the reprogramming of energy metabolism, which will provide a valuable framework to tackle changes and defects in energy metabolism that promote human fibrosis

Relevant publications: 1. Mitochondria as target to inhibit proliferation and induce apoptosis of cancer cells:

the effects of doxycycline and gemcitabine.Dijk SN, Protasoni M, Elpidorou M, Kroon AM, Taanman JW.Sci Rep. 2020 Mar 9;10(1):4363. doi: 10.1038/s41598- 020-61381-9.

2. Insights into myofibroblasts and their activation in scleroderma: opportunities for therapy?Gyftaki-Venieri DA, Abraham DJ, Ponticos M.Curr Opin Rheumatol. 2018 Nov;30(6):581-587

3. Frontiers of Antifibrotic Therapy in Systemic Sclerosis.Distler JH, Feghali-Bostwick C, Soare A, Asano Y, Distler O, Abraham DJ.Arthritis Rheumatol. 2017 Feb;69(2):257-267








Despina Eleftheriou

Position: Professor of paediatric rheumatology Location: GOSICH Research & Teaching Department Email contact: [email protected] Theme: EPM


Gene editing for deficiency of adenosine deaminase type 2 (DADA2)

Deficiency-of-adenosine-deaminase-type-2 (DADA2) is caused by bi-allelic loss-of-function mutations in ADA2. Treatment with anti-TNF is effective for the autoinflammatory/ vasculitic components of the disease but does not correct marrow failure or immunodeficiency; and anti-drug antibodies cause loss of efficacy over time. Gene therapy could be an attractive curative therapeutic option.

Rotation project

We have already demonstrated that lentiviral mediated gene addition restores ADA2 expression and function in a cell line model and macrophages from patients. However, ADA2 expression is tightly controlled, and increased ADA2 expression is seen in some cancers so concern exists that uncontrolled expression generated by lentiviral mediated gene addition could lead to further dysregulation. Gene-editing offers an alternative approach, whereby therapeutic sequences are inserted in situ, remaining under the control of the endogenous DNA regulatory mechanisms therefore providing a more optimal therapy. In this project we will develop gene -editing tools targeting the ADA2 locus, namely CRISPR-Cas9 and -Cas12a - site-specific nucleases. We will explore whether these tools can successfully mediate restoration of ADA2 expression and function in patient derived macrophages and haematopoietic stem cells (HSC). We will next explore whether gene edited HSC are capable of engrafting in murine models to restore the functional deficits associated with DADA2. This project is ideal for a PhD aimed at developing novel genetic therapeutic techniques which will require a variety of methods and disciplines. The student will join the growing critical mass of young scientists affiliated to the Autoinflammation Centre of Excellence at UCL led by the project supervisors (Brogan/Eleftheriou).


• Papadopoulou C, Harper L, Al-Abadi E, Goel R, Dubey S, Wood M, Jolles S, Berg S, Ekelund M,

Armon K, Eleftheriou D, Brogan PA. Anti-tumour necrosis factor treatment for the prevention of ischaemic events in patients with deficiency of adenosine deaminase 2 (DADA2). Cooray S, Omyinmi E, Hong Y, Rheumatology (Oxford). 2021 Jan 9:keaa837. doi: 10.1093/rheumatology/keaa837.

• Lee PY, Kellner ES, Huang Y, Furutani E, Huang Z, Bainter W, Alosaimi MF, Stafstrom K, Platt CD, Stauber T, Raz S, Tirosh I, Weiss A, Jordan MB, Krupski C, Eleftheriou D, Brogan P, Sobh A, Baz Z, Lefranc G, Irani C, Kilic SS, El-Owaidy R, Lokeshwar MR, Pimpale P, Khubchandani R, Chambers EP, Chou J, Geha RS, Nigrovic PA, Zhou Q. Genotype and functional correlates ofdisease phenotype in deficiency of adenosine deaminase 2 (DADA2).J Allergy Clin Immunol. 2020 Jun;145(6):1664- 1672.e10. doi: 10.1016/j.jaci.2019.12.908. Epub 2020 Jan 13.

• Nanthapisal S, Murphy C, Omoyinmi E, Hong Y, Standing A, Berg S, Ekelund M, Jolles S, Harper L, Youngstein T, Gilmour K, Klein NJ, Eleftheriou D, Brogan PA. Deficiency of Adenosine Deaminase Type 2: A Description of Phenotype and Genotype in Fifteen Cases.Arthritis Rheumatol. 2016 Sep;68(9):2314-22. doi: 10.1002/art.39699. PMID: 27059682



Dimitra Peppa

Position: Associate Professor in HIV Immunology Location: Institute of Immunity and Transplantation Email contact: [email protected] Theme: Experimental and Personalised Medicine

Research overview (50 words or less) The Peppa Lab focuses on human NK cell immunology studying their role in the context of HBV and HIV infection. Through the use of cutting-edge technologies, we systematically examine immune pathways that are preserved or dysregulated during viral infection to enable patient stratification for targeted interventions and development of ‘cure’ strategies.

Rotation project Among the 37 million people worldwide living HIV, as many as 7 million are co-infected with HBV. Co- infection results in accelerated HBV-related liver disease progression and increased mortality compared to mono-infection with either HIV or HBV alone. Although combined antiretroviral treatment (ART) provides benefits against both viruses, the differences in pathological disease outcome between HIV/HBV co-infected and HBV mono-infected populations persist. Prevailing wisdom holds that these distinctions arise from differences in the antiviral immune responses, particularly those localised within the liver. An integrated approach to interrogate tissue-restricted immune signatures in this understudied population of HIV/HBV co- infected patients will facilitate the development of new and safe therapeutics. This work will combine state- of-the-art molecular and immunological approaches including the use of single-cell RNA sequencing (scRNA-seq) and high-throughput single cell analysis from appropriately matched clinical cohorts. These innovative approaches will be applied to ascertain the transcriptional landscape, proteomic and functional features of immune cell populations in the liver and peripheral blood between HIV/HBV co-infected versus HBV mono-infected patients at an entirely new level of resolution. Building on our experience the candidate will i) map intrahepatic immune responses, including novel subpopulations in HBV versus HIV/HBV co- infection ii) identify pathways that modulate the activity of key immune populations, including memory NK cells and tissue resident cell subsets, and examine their antiviral potency and therapeutic utility. This level of precision immunology will offer a unique personalised approach for patients according to immunological phenotypes and viral characteristics.


1. Maini MK and Peppa D. Shared immunotherapeutic approaches in HIV and HBV: Combine and Conquer. Current Opinion in HIV and AIDS. 2020

2. Bradley T*, Peppa D* et al. RAB11FIP5 expression and altered natural killer cell function are associated with induction of HIV broadly neutralizing antibody responses, Cell 2018 Oct 4;175(2):387- 399e17

3. Huang WC et al T Cells Infiltrating Diseased Liver Express Ligands for the NKG2D Stress Surveillance System. J Immunol. 2017 Feb 1;198(3):1172-1182.

4. Stegmann KA, Robertson F, Hansi N, Gill U, Pallant C, Christophides T, Pallett LJ, Peppa D, Dunn C, Fusai G, Male V, Davidson BR, Kennedy P, Maini MK. CXCR6 marks a novel subset of T- bet(lo)Eomes(hi) natural killer cells residing in human liver. Sci Rep. 2016 May 23;6:26157.

5. Peppa D, Gill US, Reynolds G, Easom NJ, Pallett LJ, Schurich A, Micco L, Nebbia G, Singh HD, Adams DH, Kennedy PT, Maini MK. Up-regulation of a death receptor renders antiviral T cells susceptible to NK cell-mediated deletion. J Exp Med. 2013 Jan 14;210(1):99-114.


https://www.ncbi.nlm.nih.gov/pubmed/27210614





Siobhan Burns and Emma Morris

Position: Professor of Translational Immunology and Professor of Cell and Gene Therapy Location: Institute of Immunity and Transplantation Email contact: [email protected] or [email protected] Theme: Experimental and Personalised Medicine.


Towards Gene Editing for Inherited Immunodeficiencies: Assessment & correction of novel disease- causing LRBA variants.

LPS-responsive beige-like anchor (LRBA) deficiency is a severe inherited primary immunodeficiency disorder (PID) characterised by infection associated with autoimmune and inflammatory complications1,2,3.Current treatment options are limited3,4,5,6. This project will develop and test gene editing approaches to correct mutations that give rise to LRBA deficiency.

Rotation project

At UCL, we have the largest cohort of paediatric and adult patients with inherited immunodeficiencies in Europe and have been at the forefront of developing novel gene therapy approaches for these diseases. This project will focus on a specific disorder as a model for difficult-to-treat immunodeficiency conditions and will form part of a portfolio of studies in our research group.

Using our established cell lines, we will initiate pre-clinical development and testing of two CRISPR/CAS9 gene editing approaches to: 1. Correct the specific missense defects and restore wild type LRBA sequence 2. Confirm functional correction of immune cell subsets

To do this, we will utilise a base editing approach to specifically correct individual LRBA mutations. We will demonstrate restoration of LRBA expression using western blotting/confocal microscopy and flow cytometry. As LRBA -deficiency results in disrupted lysosome-associated trafficking of the important immune regulator CTLA-4 to the T-cell surface1,7,8,9, we will measure CTLA-4 expression and recycling using well established assays before and after gene correction.

Relevant publications 1. Lopez-Herrera G, Tampella G, Pan-Hammarstrom Q, et al. Deleterious mutations in LRBA are associated with a syndrome of immune deficiency and autoimmunity. Am J Hum Genet. 2012;90(6):986-1001. 2. Burns SO, Zenner HL, Plagnol V, et al. LRBA gene deletion in a patient presenting with autoimmunity without hypogammaglobulinemia. J Allergy Clin Immunol. 2012. 3. Kostel Bal S, Haskologlu S, Serwas NK, et al. Multiple Presentations of LRBA Deficiency: a Single-Center Experience. J Clin Immunol. 2017;37(8):790-800. 4. Gamez-Diaz L, August D, Stepensky P, et al. The extended phenotype of LPS-responsive beige-like anchor protein (LRBA) deficiency. J Allergy Clin Immunol. 2016;137(1):223-230. 5. Tesi B, Priftakis P, Lindgren F, et al. Successful Hematopoietic Stem Cell Transplantation in a Patient with LPS-Responsive Beige-Like Anchor (LRBA) Gene Mutation. J Clin Immunol. 2016;36(5):480-489. 6. Seidel MG, Hirschmugl T, Gamez-Diaz L, et al. Long-term remission after allogeneic hematopoietic stem cell transplantation in LPS-responsive beige-like anchor (LRBA) deficiency. J Allergy Clin Immunol. 2015;135(5):1384-1390.e1381-1388. 7. Lo B, Zhang K, Lu W, et al. AUTOIMMUNE DISEASE. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy. Science. 2015;349(6246):436-440. 8. Gamez-Diaz L, Neumann J, Jager F, et al. Immunological phenotype of the murine Lrba knockout. Immunol Cell Biol. 2017;95(9):789-802. 9. Burnett DL, Parish IA, Masle-Farquhar E, Brink R, Goodnow CC. Murine LRBA deficiency causes CTLA-4 deficiency in Tregs without progression to immune dysregulation. Immunol Cell Biol. 2017;95(9):775-788.




Gavin Jell

Position: Associate Professor Location: Royal Free Campus Email contact: [email protected] Theme: Experimental and Personalised Medicine (EPM)

Research overview: Bone tissue engineering for diabetic patients via HIF

This project investigates if the controlled release of Hypoxia Inducible Factors (HIF) from materials can restore healthy bone remodelling and regeneration in diabetic models.

Rotation project:

Diabetic patients have an increased occurrence of bone fracture, higher orthopaedic implant failure rates and impaired fracture healing. Diabetic patients also have a reduced (cellular) ability to sense hypoxia (a drop in oxygen pressure). When designing materials or regenerative medicines, the bone tissue engineering and bone graft communities have failed to consider underlying bone disease and differences in bone metabolism. There is, therefore, an urgent need to develop new bone regenerative materials that have better control of both osteoclast and osteoblast behaviour in these patients.

Using a unique in vitro model, our group has recently demonstrated that high glucose environments inhibit osteoclast formation. This rotation project will investigate if HIF-1alpha mimetics can restore osteoclast functionality in these in vitro diabetic conditions. The student will develop a wide range of interdisciplinary skills at the interface between biology and material science, including: 1) high resolution imaging and characterisation of in vitro osteoclast formation and activity (using the newly developed physicochemical imaging suite within the Royal Free); 2) advanced in vitro cell culture (TRAP-5b, in vitro bone resorption, HIF-1alpha stabilisation).

Gavin Jell. 40+ high-impact publications (e.g. Nature Materials) on bone tissue engineering and multidisciplinary in vitro characterisation. The student will be supported by 2PhDs and 1PDRA’s working in similar areas. Gavin is a UKCGE Recognised Research Supervisor and nominated twice for the “Outstanding Research Supervision” award.

Relevant publications Taheem, D (2020). Hypoxia Inducible Factor-1α in Osteochondral Tissue Engineering. Tissue Engineering Part B: Reviews. doi:10.1089/ten.TEB.2019.0283

Taheem, D (2018). Differential Regulation of Human Bone Marrow Mesenchymal Stromal Cell Chondrogenesis by Hypoxia Inducible Factor-1α Hydroxylase Inhibitors. Stem cells. doi:10.1002/stem.2844

Quinlan, E (2015) Hypoxia-mimicking bioactive glass/collagen glycosaminoglycan composite scaffolds to enhance angiogenesis and bone repair. 2015. Biomaterials 52

Azevedo, M (2015) HIF-stabilizing bioactive glasses for directing MSC behaviour 2015, Tissue Engineering. Part A.

Maes, C (2012) Hypoxia-driven pathways in bone development.. Nature Rev Rhe. 8, 358. X. Shen (2009). PHD inhibitors increase neoangiogenesis and callus formation, J. Ortho. Res

1298.


https://www.researchgate.net/researcher/2049282222_Elaine_Quinlan

https://www.researchgate.net/publication/273207256_Hypoxia-mimicking_bioactive_glasscollagen_glycosaminoglycan_composite_scaffolds_to_enhance_angiogenesis_and_bone_repair?ev=prf_pub

https://www.researchgate.net/publication/273207256_Hypoxia-mimicking_bioactive_glasscollagen_glycosaminoglycan_composite_scaffolds_to_enhance_angiogenesis_and_bone_repair?ev=prf_pub


Georgia Black

Position: Principal Research Fellow Location: Department of Applied Research Email contact: [email protected] Theme: Early diagnosis of cancer


Many cancer patients experience symptoms that seem normal, or appear to be caused by other, non-serious diseases. Clinical uncertainty is therefore an inevitability for GPs who must manage non-specific symptoms without provoking unnecessary delays in diagnosis. Diagnostic uncertainty can affect the patient, the health system, and induce stress for clinicians.

Rotation project This project would suit a student who is interested in exploring qualitative methods in their PhD (no prior experience necessary – training can be provided) and enjoys working in applied settings with clinical collaborators. The placement is in the Department of Applied Health Research in a team that aims to increase patient safety and reduce delays in cancer diagnosis. The placement is relevant to students interested in diagnostic error, primary care, quality and safety of care, patient communication and health psychology.

Contributing to a qualitative study around the management of diagnostic uncertainty in primary care using existing video and interview data.

• Liaising with collaborating academic teams in University of Surrey and Baylor College of Medicine, Texas, USA.

Depending on the interest and learning needs of the student, there is opportunity to:

• Take an active role in working with cancer alliances to develop implementable strategies to improve the management of diagnostic uncertainty.

• For example, advising on the use of electronic safety netting tools to manage diagnostic uncertainty.

• Contribute to academic papers and conference presentations.

• Contribute to other ongoing qualitative studies in the department on the topic of early diagnosis of cancer.


Amelung, D., Whitaker, K.L., Lennard, D., Ogden, M., Sheringham, J., Zhou, Y., Walter, F.M., Singh, H., Vincent, C. and Black, G., 2020. Influence of doctor-patient conversations on behaviours of patients presenting to primary care with new or persistent symptoms: a video observation study. BMJ quality & safety, 29(3), pp.198-208.

Piano, M., Black, G., Amelung, D., Power, E. and Whitaker, K.L., 2019. Exploring public attitudes towards the new Faster Diagnosis Standard for cancer: a focus group study with the UK public. British Journal of General Practice, 69(683), pp.e413-e421.



Dr Hayley Whitaker

Position: Associate Professor in Cancer Biology Location: Charles Bell House, 43-45 Foley Street, London, W1W 7TS Email contact: [email protected]

Theme: Experimental and Personalised Medicine (EPM)


My research group includes a mixture of basic, translational and clinical researchers at all levels working on projects aimed at improving the diagnosis and treatment of cancer. The rotation project builds upon previous work in the lab and a collaboration with the university of Cambridge.

Rotation project PROteolysis TArgeting Chimeras (PROTACs) are a revolutionary way to target proteins associated with disease for degradation as a therapeutic strategy. PROTACs are hetero bifunctional molecules that connect a ligand to an E3 ubiquitin ligase (E3) recruiting ligand with an optimised linker. In the field of prostate cancer dihydrotestosterone (DHT) is used as the ligand to target the androgen receptor (AR) for degradation. The advantage of PROTACs is that they can be taken orally and are readily bioavailable. The AR-targeting PROTAC ARV-110 which utilises DHT has a ligand has recently completed successful Phase I trials. In collaboration with the University of Cambridge we aim to test a range of novel PROTACs for their ability to degrade the AR in our cell line systems. The project will also build on previous work to identify the optimal E3 ligases for PROTACs in prostate cancer.

Objectives/skills

• Assessment of AR degradation in cell lines treated with PROTACs using tissue culture,

Western blotting and image analysis.

• Assessment of E3 ligase expression in a range of cell lines using tissue culture, qPCR

and Western blotting.

• If time permits PROTACS will be tested on ex-vivo primary tissue


Salami, J., Alabi, S., Willard, R.R. et al. Androgen receptor degradation by the proteolysis- targeting chimera ARCC-4 outperforms enzalutamide in cellular models of prostate cancer drug resistance. Commun Biol 1, 100 (2018). https://doi.org/10.1038/s42003-018-0105-8

Dhanusha A Nalawansha, Craig M Crews. PROTACs: An Emerging Therapeutic Modality in Precision Medicine. Cell Chem Biol. 2020 Aug 20;27(8):998-1014. doi:10.1016/j.chembiol.2020.07.020.

Duncan Scott, Timothy Rooney, Elliott Bayle, et al.; Systematic Investigation of the Permeability of Androgen Receptor PROTACs. ACS Med. Chem. Lett. 2020, 11, 8, 1539– 1547



Professor Hilali Noordeen

Position: Consultant Spinal Surgeon Location: Royal National Orthopaedic Hospital Email contact: [email protected] Theme: Experimental and Personalised Medicine (EPM)


New/persistent back pain is a common complication post-spinal surgery and is thought to arise from scarring and fibrosis around the spinal nerves. Retinoids have been shown to be effective in preventing and reducing scarring and fibrosis in multiple organ systems. We are conducting a clinical trial investigating retinoids on post-operative pain.

Rotation project

Students will be joining the team in an early-stage Phase 2 double-blinded randomised controlled clinical trial titled “Retinoids in Post-Operative SpinE pain” (REPOSE trial). This multicentre trial is a joint venture between University College London and University of Oxford. This will give invaluable experience and insight in conducting and running clinical trials. The trial drug has been given MHRA approval and the trial protocol has been written.

Specific skills that may be gained include project write up, patient recruitment, data handling, statistical analysis, adverse event monitoring and more. Students will also obtain an appreciation on the mechanisms of pain, regenerative medicine, spinal surgery and retinoid biology.

This is an exciting field as post-operative pain is prevalent across different surgical specialties and the outcomes of this trial will have good generalisability to those other specialties.


1) Zhang, C. et al. (2014) ‘All-trans retinoic acid prevents epidural fibrosis through NF-

κB signaling pathway in post-laminectomy rats’, Neuropharmacology. Elsevier Ltd, 79, pp. 275–281. doi: 10.1016/j.neuropharm.2013.11.010.

2) Mey, J. (2006) ‘New therapeutic target for CNS injury? The role of retinoic acid signaling after nerve lesions’, Journal of Neurobiology, pp. 757–779. doi: 10.1002/neu.20238.

3) Mey, J. (2001) ‘Retinoic acid as a regulator of cytokine signaling after nerve injury’, Zeitschrift fur Naturforschung - Section C Journal of Biosciences. Verlag der Zeitschrift fur Naturforschung, 56(3–4), pp. 163–176. doi: 10.1515/znc-2001-3-401.



Dr Hirak K Patra

Position: Associate Professor of Nanomedicine and Regenerative Medicine Location: DSIS, University College London Email contact: [email protected] Theme: Personalised Medicine

Research overview (50 words or less) :Corneal disease is one of the major causes of blindness, where transplantation with a donor cornea is the only current option. However, the demands completely outpace the supply (1 available when 70 needs). We will develop cell-free pro-regenerative collagen based corneal implants for custom-fit personalised medicine to help the functional regeneration to restore vision.

Rotation project :During the project rotation the student will develop Pro-Regenerative Artificial Cornea (PRAC) using collagen. Personalised PRAC will be pre-medicated by embedding nanosystems to combat one’s specific challenges associated with graft rejection (e.g., inflammation, infection etc). We have structure the rotation in 3 major components:

1. Literature review and experimental design (2-3 weeks) - Guided literature review and discussion with the PIs and members of the labs - Opportunity to present experimental plan (and results in subsequent meetings)

2. Developing and optimising nanosystems to embed in the implants (3-4 weeks) - Nanogel fabrication: ECM based (e.g., collagen, hyaluronic acid) nanohydrogel (NH) will be synthesised and loaded with

drugs to embed within the implants. - Characterisation of NH: Nano size distribution, charge, morphology, drug release and drug efficacy will be characterised

using, Dynamic Light Scattering (DLS), Nanoparticle Tracking Analysis (NTA), Electron Microscopy (EM) etc.

3. Implant fabrication and functionalisation (4-6 weeks) - Implant fabrication: Corneal shaped collagen implants will be fabricated with different thickness and with the embedded

NH system. - Implant characterisation: Corneal implants will be tested with optical clarity, biocompatibility with human corneal cells,

mechanical property etc.

4. Presentation of final results and rotation project write-up (2-3 weeks) - Guided thesis write-up with regular feedback - Presentation of final results in regular research group data club

We have designed the programme with the aim that the student (s) will acquire both specific research skills in nanomedicine and a broader portfolio of transferable skills in the area of personalised regenerative medicines. We strongly believe that will prepare them for their future professions and facilitate their succession as leading researcher.


• Patra, H. K., Azharuddin, M., Islam, M. M., Papapavlou, G., Deb, S., Osterrieth, J.,..Slater, N. K. H. (2019). Rational Nanotoolbox with Theranostic Potential for Medicated Pro-Regenerative Corneal Implants. ADVANCED FUNCTIONAL MATERIALS, 29 (38), ARTN 1903760. doi:10.1002/adfm.201903760

• Buznyk, O., Azharuddin, M., Islam, M. M., Fagerholm, P., Pasyechnikova, N., & Patra, H. K. (2020). Collagen-based scaffolds with infused anti-VEGF release system as potential cornea substitute for high-risk keratoplasty: A preliminary in vitro evaluation. Heliyon, 6 (10), e05105. doi:10.1016/j.heliyon.2020.e05105

• Sharifi, S., Islam, M. M., Sharifi, H., Islam, R., Huq, T. N., Nilsson, P. H.,..Chodosh, J. (2021). Electron Beam Sterilization of Poly(Methyl Methacrylate)—Physicochemical and Biological Aspects. Macromolecular Bioscience. doi:10.1002/mabi.202000379

• Zhu, G. H., Azharuddin, M., Islam, R., Rahmoune, H., Deb, S., Kanji, U.,…Patra, H. K. (2021). Innate Immune Invisible Ultrasmall Gold Nanoparticles-Framework for Synthesis and Evaluation. ACS Applied Materials and Interfaces. doi:10.1021/acsami.1c02834

• Islam MM, AbuSamra DB, Chivu A, Argüeso P, Dohlman CH, Patra HK, Chodosh J, González-Andrades M. Optimization of Collagen Chemical Crosslinking to Restore Biocompatibility of Tissue-Engineered Scaffolds. Pharmaceutics. 2021; 13(6):832. https://doi.org/10.3390/pharmaceutics13060832

• Lin, Q., Qu, M., Zhou, B., Patra, H. K., Sun, Z., Luo, Q.,…Zhang, Z. (2019). Exosome-like nanoplatform modified with targeting ligand improves anti-cancer and anti-inflammation effects of imperialine. JOURNAL OF CONTROLLED RELEASE, 311, 104-116. doi:10.1016/j.jconrel.2019.08.037



Ines Pineda-Torra/ Liz Jury

Position: Prof in Cardiometabolic Medicine (IPT)/ Prof in Experimental Rheumatology (LJ) Location: Rayne Building, Bloomsbury Campus Email contact: [email protected] Theme: Experimental and personalised Medicine

Research overview (50 words or less) Traditionally, cardiovascular disease (CVD), was considered to predominantly affect men. Consequently, women have been understudied, underdiagnosed and undertreated. Importantly, women with autoimmune diseases show significantly increased cardiovascular risk compared to the general population. However, despite CVD being a major cause of morbidity and mortality for these women, this increased risk is not managed clinically using existing therapies and tools to dissect and predict their cardiovascular risk are lacking.

Rotation project To identify mechanisms explaining increased CVD risk in SLE women, we have generated biochemical and genomic information of a well-phenotyped cohort of CVD-free women with SLE, scanned for atherosclerosis (most prevalent pathology underlying CVD). Using state-of-the-art methodologies we now have global profiles of a) circulating metabolites b) circulating proteins and c) monocyte expression profiles (1,2 and unpublished results). Contrary to existing knowledge derived from mouse studies, CD8+T-cells were recently shown to be the most abundant cell type in human atherosclerotic plaques (>30%), but their role in SLE-related atherosclerosis remains largely unknown. We have a long-standing interest in the regulation of lipid metabolism in CD4+ and CD8+ that could impact the progression of metabolic and autoimmune diseases such as SLE (3). We recently showed that CD8+T-cells are significantly increased in Juvenile-onset SLE patients and are predictive of a worsened disease prognosis (4).

From the same adult SLE cohort we isolated CD4+ and CD8+ T cells and have now generated global gene expression profiles by RNA sequencing. The student will be in charge of analysing them and putting them in the context of other published datasets and existing literature. Specifically, the aims will be to: 1) Identify specific and common gene expression profiles between CD4+, CD8+ and monocytes associated with the presence of atherosclerosis in the same cohort through pathway analysis and advance network exploration. 2) Identify associations between these gene signatures and circulating metabolites associated with atherosclerosis or with the persistent absence of atherosclerosis in these women 3) Identify associations between these gene signatures and protein profiles

The student will learn a series of bioinformatic and statistical tools including: pathway analysis (GSEA, Metascape), visualisations tools (heatmaps and volcano plots), network analyses

Relevant publications 1. L Coelewij, KE Waddington, GA Robinson, …., A Rahman, EC Jury*, I Pineda-Torra* (2021) Serum Metabolomic Signatures Can Predict Subclinical Atherosclerosis in Patients With Systemic Lupus Erythematosus, Arteriosclerosis, Thrombosis, and Vascular Biology, Feb 1:ATVBAHA120315321. DOI: 10.1161/ATVBAHA.120.315321

2. Woodridge L, … Rahman A, Orengo C, Jury EC, Pineda-Torra I. (2020), Unique monocyte transcriptomic profiles are associated with preclinical atherosclerosis in women with systemic lupus erythematosus (SLE), medRxiv, https://doi.org/10.1101/2020.08.05.20169136

3. Waddington KE, Robinson G, …, Jury EC*, Pineda-Torra I* (2021). LXR directly regulates glycosphingolipid synthesis and affects human CD4+ T cell function. Proc Natl Acad Sci U S A. 2021 May 25;118(21):e2017394118. https://doi.org/10.1073/pnas.2017394118

4. Robinson GA, Coelewij L, … Ciurtin C*, Pineda-Torra *, Jury EC* (2021) Increased apolipoprotein- B:A1 ratio predicts cardiometabolic risk in patients with juvenile onset SLE, EBioMedicine, Volume 0, Issue 0, 103243, DOI: https://doi.org/10.1016/j.ebiom.2021.103243


https://doi.org/10.1161/atvbaha.120.315321

https://www.medrxiv.org/content/10.1101/2020.08.05.20169136v1.abstract



https://doi.org/10.1101/2020.08.05.20169136

https://doi.org/10.1073/pnas.2017394118

https://doi.org/10.1016/j.ebiom.2021.103243


Joe Standing

Position: Professor of Pharmacometrics Location: GOSICH Research & Teaching Department Email contact: [email protected] Theme: EPM


SARS-CoV-2 viral dynamic modelling to guide antiviral drug development

The SARS-CoV-2 pandemic has exposed a lack of potent antiviral agents, and knowledge on how best to develop and deploy them. To understand viral dynamics and biomarkers of pharmacological effect in early disease will guide therapeutic strategies to prevent disease progression. Mathematical modelling and/or in vitro virology will be used.

Rotation project

This work will focus on antiviral drug development. Pre-clinical antiviral combination screening and mathematical modelling of SARS-CoV-2 viral dynamics in vivo will be used to optimally design and analyse the results of Phase II trials. Viral load changes by the hour: after initial infection viral load in the nose and throat rises to a peak around the time of symptom onset, and then falls away again such that by Day 7 up to a third of people no longer have detectable virus. Viral load trajectories also differ in patients of different age, disease severity, and viral variant. Therefore a mathematical model of the expected time course is needed to tease out drug effects from these other variables. Furthermore, the decline in viral load is driven at least in part by release from infected cells, it may not be truly representative of antiviral drug activity. We will also look at biomarkers derived from viral whole genome sequencing.

Using data from our individual patient-level meta analysis, and our in vitro combination screening, models will be developed and applied to analyse two ongoing Phase II trials, FLARE and FANTAZE, (both are double blind randomised trials with daily viral loads and whole genome viral sequencing).

Figure 1: Model-based prediction of viral load with time since symptom onset. Percentage of expected below limit of detection samples given for each 2-day time bin.

Relevant publications Brown LK et al. Early antiviral treatment in outpatients with COVID-19 (FLARE): a structured summary of a study protocol for a randomised controlled trial. Trials. 2021 Mar 8;22(1):193. doi: 10.1186/s13063-021-05139- 2.

Gastine S et al. Systematic Review and Patient-Level Meta-Analysis of SARS-CoV-2 Viral Dynamics to Model Response to Antiviral Therapies. Clin Pharmacol Ther. 2021 Feb 28:10.1002/cpt.2223. doi: 10.1002/cpt.2223.

Zeitlinger M, et al Pharmacokinetics/Pharmacodynamics of Antiviral Agents Used to Treat SARS-CoV-2 and Their Potential Interaction with Drugs and Other Supportive Measures: A Comprehensive Review by the PK/PD of Anti-Infectives Study Group of the European Society of Antimicrobial Agents. Clin Pharmacokinet. 2020 Oct;59(10):1195-1216. doi: 10.1007/s40262-020-00924-9.



Dr John Counsell

Position: Senior Research Fellow Location: GOSICH Research & Teaching Department Email contact: [email protected] Theme: EPM

Research overview (50 words or less) Engineering next-generation gene therapy vectors with enhanced nuclear localisation Gene therapy vectors are now being used in a variety of settings, such as treating monogenic diseases and more recently in vaccination against pandemic diseases. This project aims to develop enhanced gene therapies engineered for precise interactions with cellular proteins for optimal entry and distribution within the nucleus.

Rotation project Aims: To develop DNA gene transfer vectors that engage with host proteins to gain efficient entry to the nucleus and interactions with RNA polymerase complexes. Need: Gene therapy vectors are commonly based on viruses, as they are very efficient at getting DNA into the nucleus. But viral components can trigger many innate and adaptive immune defences, which bring unwanted side effects. Additionally, many forms of viral vector DNA do not express therapeutic genes efficiently in treated cells. This means that high doses of these viruses are often required for achieving treatment thresholds. Our research group is focused on developing novel vector technologies that achieve efficient gene expression with minimal viral components, for a cleaner medicinal product. Experimental plan: The student will develop novel DNA gene transfer vectors for enhanced trafficking to the cell nucleus. Techniques will include molecular cloning of DNA constructs and cell culture to engineer novel vector technologies, electron microscopy and super resolution imaging to model vector trafficking to the nucleus, and flow cytometry and bioimaging to measure the level of transgene expression in treated cells.

Relevant publications Perocheau, D. P., Mock, U., & Waddington, S. N. (2021). Re-structuring lentiviral vectors to express genomic

RNA via cap-dependent translation. Molecular Therapy - Methods & Clinical Development, 20, 357–365. https://doi.org/10.1016/j.omtm.2020.12.005

Counsell, J. R., Karda, R., Diaz, J. A., Carey, L., Wiktorowicz, T., Buckley, S. M. K., Ameri, S., Ng, J., Baruteau, J., Almeida, F., de Silva, R., Simone, R., Lugarà, E., Lignani, G., Lindemann, D., Rethwilm, A., Rahim, A. A., Waddington, S. N., & Howe, S. J. (2018). Foamy Virus Vectors Transduce Visceral Organs and Hippocampal Structures following In Vivo Delivery to Neonatal Mice. Molecular Therapy. Nucleic Acids, 12, 626–634. https://doi.org/10.1016/j.omtn.2018.07.006

Karda, R., Rahim, A. A., Suff, N., Diaz, J. A., Perocheau, D. P., Martin, N. P., Hughes, M., Delhove, J., Counsell, J. R., Henckaerts, E., Mckay, T. R., Buckley, S. M. K., & Waddington, S. N. (2018). Generation of Light-Producing Somatic-Transgenic Mice Using Adeno-Associated Virus Vector. In MOLECULAR THERAPY (Vol. 26, Issue 5, p. 40). CELL PRESS. http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&Src Auth=LinksAMR&KeyUT=WOS:000435342200081&DestLinkType=FullRecord&DestApp=ALL_WOS&Usr CustomerID=f41074198c063036414efcbc916f8956

Ng, J., Barral, S., De La Fuente Barrigon, C., Lignani, G., Erdem, F. A., Wallings, R., Privolizzi, R., Rossignoli, G., Alrashidi, H., Heasman, S., Meyer, E., Ngoh, A., Pope, S., Karda, R., Perocheau, D., Baruteau, J., Suff, N., Antinao Diaz, J., Schorge, S., … Kurian, M. A. (2021). Gene therapy restores dopamine transporter expression and ameliorates pathology in iPSC and mouse models of infantile parkinsonism. Science Translational Medicine, 13(594), eaaw1564. https://doi.org/10.1126/scitranslmed.aaw1564

Rossignoli, G., Krämer, K., Lugarà, E., Alrashidi, H., Pope, S., De La Fuente Barrigon, C., Barwick, K., Bisello, G., Ng, J., Counsell, J., Lignani, G., Heales, S. J. R., Bertoldi, M., Barral, S., & Kurian, M. A. (2021). Aromatic l-amino acid decarboxylase deficiency: a patient-derived neuronal model for precision therapies. Brain. https://doi.org/10.1093/brain/awab123

Vink, C. A., Counsell, J. R., Perocheau, D. P., Karda, R., Buckley, S. M. K. K., Brugman, M. H., Galla, M., Schambach, A., McKay, T. R., Waddington, S. N., & Howe, S. J. (2017). Eliminating HIV-1 Packaging Sequences from Lentiviral Vector Proviruses Enhances Safety and Expedites Gene Transfer for Gene Therapy. Molecular Therapy, 9(0), 10–20. https://doi.org/10.1016/j.ymthe.2017.04.028


http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&Src


Karin Tuschl

Position: MRC Clinician Scientist Fellow Location: GOSICH Research & Teaching Department Email contact: [email protected] Theme: Experimental and personalised medicine


Developing antisense oligonucleotide therapy to reduce manganese brain accumulation in disorders associated with manganese neurotoxicity.

Using mouse and zebrafish models of manganese overload, this research focuses on the disease mechanisms underlying inherited manganese transporter defects, a group of disabling, neurological childhood disorders. Thereby, we aim to identify new treatment approaches for manganese neurotoxicity

including antisense oligonucleotides and metal specific chelators to reduce manganese brain uptake.

Rotation project Manganese is an essential trace metal and critical for brain physiology. At the same time, manganese overload is neurotoxic and causes a disabling movement disorder known as manganism. Manganese neurotoxicity is a key feature of inherited manganese transporter defects caused by mutations in the cell membrane transporters SLC30A10 and SLC39A14 that lead to impaired manganese excretion and progressive, childhood-onset dystonia-parkinsonism. Current treatment is limited to intravenous chelation therapy with EDTA which is both burdensome and associated with adverse effects. During the rotation project, the student will test the hypothesis that reducing manganese brain uptake using antisense oligonucleotides to knockdown SLC39A8, a manganese uptake transporter, can prevent manganese overload in cell culture. The student will design antisense oligonucleotides that target both human and murine SLC39A8 mRNA and assess their efficacy in human fibroblasts and murine 3T3 cells using qPCR, Western blotting and immunofluorescence staining. During the rotation project, the student will gain knowledge in manganese metabolism and be trained in molecular biology and cell culture protocols. The results obtained will form the foundations for a proof-of- concept study in mice that will assess the efficacy of antisense oligonucleotides and novel chelators in the Slc30a10 knockout mouse, a disease model of manganese neurotoxicity.


1. Tuschl K et al. Maintaining Translational Relevance in Animal Models of Manganese Neurotoxicity. J Nutr. 2020;150:1360-1369.

2. Aguti S et al. Exon-Skipping Oligonucleotides Restore Functional Collagen VI by Correcting a Common COL6A1 Mutation in Ullrich CMD. Mol Ther Nucleic Acids. 2020;21:205-216.

3. S. Anagianni, K. Tuschl, Genetic Disorders of Manganese Metabolism, Curr Neurol Neurosci Rep, 19 (2019) 33.

4. Tuschl K et al. Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism-dystonia. Nat Comms. 2016. 7:11601.

5. Tuschl K et al. Syndrome of hepatic cirrhosis, dystonia, polycythaemia and hypermanganesaemia – caused by mutations in SLC30A10, a manganese transporter in man. Am J Hum Genet. 2012. 90:457- 466



Maelle Lorvellec

Position: Research Associate in Prof. Paul Gissen’s Laboratory Location: GOSICH Research & Teaching Department Email contact: [email protected] Theme: Experimental and personalised medicine

Research overview (50 words or less) Lentiviral based gene therapy for Arthrogryposis Renal dysfunction and Cholestasis syndrome in kidney cells

Arthrogryposis Renal dysfunction Cholestasis (ARC) syndrome is a rare metabolic disease affecting multiple organs such as kidneys, liver, skin and platelets. This project will use lentiviral vector gene therapy to treat ARC kidney cells.

Rotation project Arthrogryposis Renal dysfunction Cholestasis (ARC) syndrome is an autosomal recessive multisystem disorder. ARC is caused by deficiencies of VPS33B or VIPAR. Affected infants usually die in the first year of life. VPS33B and VIPAR form a stable complex and direct trafficking of intracellular proteins in a various organs including kidneys, liver and bone marrow. No specific medical treatment is currently available, hence the need to develop new therapies. We are investigating lentiviral vector-based gene therapy which can be delivered either in vivo or ex vivo as a form of autologous bone marrow transplantation. Stable knockdown of Vps33b in mouse inner medullary collecting duct cells (mIMCD-3) display clear phenotype including abnormal expression of membrane proteins, increased collagen IV expression and abnormal cell polarisation. In this rotation project the student will test VPS33B transgene containing lentiviral gene therapy vector in mIMCD3 cells. The objectives of the project are: 1) Production of the hVPS33B containing lentiviral vector with/out a fusion with a fluorophore such as eGFP. 2) 3D culture of mIMCD3 with stable Vps33b knockdown treated with gene therapy vectors. 3) Testing Vps33b expression in mIMCD3 using real-time PCR and western blotting. 4) Imaging of cell polarisation by confocal microscopy.


Banushi, B., Forneris, F., Straatman-Iwanowska, A., Strange, A., Lyne, A. M., Rogerson, C., Burden, J. J., Heywood, W. E., Hanley, J., Doykov, I., et al. (2016). Regulation of post-Golgi LH3 trafficking is essential for collagen homeostasis. Nat Commun, 7, 12111.

Cullinane, A. R., Straatman-Iwanowska, A., Zaucker, A., Wakabayashi, Y., Bruce, C. K., Luo, G., Rahman, F., Gurakan, F., Utine, E., Ozkan, T. B., et al. (2010). Mutations in VIPAR cause an arthrogryposis, renal dysfunction and cholestasis syndrome phenotype with defects in epithelial polarization. Nat Genet, 42, 303- 312.

Gissen, P., Tee, L., Johnson, C. A., Genin, E., Caliebe, A., Chitayat, D., Clericuzio, C., Denecke, J., Di Rocco, M., Fischler, B., et al. (2006). Clinical and molecular genetic features of ARC syndrome. Hum Genet, 120, 396-409.

Hanley, J., Dhar, D. K., Mazzacuva, F., Fiadeiro, R., Burden, J. J., Lyne, A. M., Smith, H., Straatman- Iwanowska, A., Banushi, B., Virasami, A., et al. (2017). Vps33b is crucial for structural and functional hepatocyte polarity. J Hepatol, 66, 1001-1011.

Vink, C. A., Counsell, J. R., Perocheau, D. P., Karda, R., Buckley, S. M. K., Brugman, M. H., Galla, M., Schambach, A., Mckay, T. R., Waddington, S. N., et al. (2017). Eliminating HIV-1 Packaging Sequences from Lentiviral Vector Proviruses Enhances Safety and Expedites Gene Transfer for Gene Therapy. Mol Ther, 25, 1790-1804



Prof Mala Maini (Primary Supervisor) Dr Laura Pallett (Secondary Supervisor)

Position: Group Lead Location: Pears Building, Institute of Immunity & Transplantation Email contact: [email protected] ([email protected]) Theme: Experimental and Personalised Medicine (EPM)

Research overview (50 words or less) Research focus: Understanding the cellular interaction and communication between tissue resident T cells (TRM) and the underlying stromal cell network. Specifically, exploring how this “conversation” cross- regulates cellular localisation, survival, function and fibrogenic potential to exacerbate (or limit) the development of liver fibrosis. Our work ultimately addresses fundamental questions in liver-resident T cell and stromal cell biology to provide evidence to support the development of novel therapeutic strategies.

Rotation project The liver is a unique environment, tolerised to avoid excessive responses against harmless antigens, whilst retaining an ability to mount an immune response to insult or injury. Our previous studies have highlighted the importance of specialised tissue-resident T cells (TRM), that do not recirculate and reside permanently in the liver. These ‘frontline sentinels’ mediate rapid responses against invading pathogens and cancer, leading to great interest in harnessing TRM as targets for vaccination and immunotherapy. However more recently, reports have emerged in other organs suggesting that TRM may also play a role in regulating tissue-specific damage.

This rotation project will explore potential axes that regulate T cell retention and in situ localisation in the human liver in in health and disease. This joint project between the Maini lab and the Pallett lab will work alongside the Tissue Access for Patient Benefit Initiative (IIT; Royal Free Hospital) to unravel the expression pattern of adhesion molecules tethering human liver-resident T cells (TRM) to the underlying stromal cell network. Within the rotation project, we will compare the liver-TRM phenotype and function from patients with histologically normal livers, those with mild-moderate fibrosis and those with advanced cirrhosis, as a model in which liver-infiltrating and liver-resident T cells can be evaluated at various stages of stromal cell/myofibroblast differentiation. We postulate that the process of myofibroblast differentiation and the dysregulated secretion of ECM, characteristic of tissue fibrosis, serves as an axis for the control of TRM frequency, phenotype and function. As part of the team, you will liaise with clinical colleagues, process primary tissue samples and use state-of-the-art multiparametric flow cytometry to interrogate immunological data. All data will be further assessed by correlating findings with clinical parameters including the underlying disease aetiology, the extent of liver inflammation, and/or the age/gender of the patient to gain initial insights into the functional role of TRM in fibrosis.


1. Pallett L.J. et al JEM 2017 “IL-2high tissue-resident T cells in the human liver: Sentinels for hepatotropic infection”

2. Gill U.S. & Pallett L.J. et al Gut 2019 “Fine needle aspirates comprehensively sample intrahepatic immunity”

3. Pallett L.J. & Burton A.R. et al JEM 2020

“Longevity and replenishment of human liver-resident memory T cells and mononuclear phagocyte”




Mark Hamer

Position: Professor Sport & Exercise Medicine Location: Institute Sport Exercise Health/ RDTI Email contact: [email protected] Theme: EPM


Wearable technology is becoming more affordable and presents an opportunity to develop personalised medicine approaches. In particular, accelerometry devices can capture fine grained data on physical behaviours such as exercise, sedentary time, and sleep. Interventions to improve physical behaviours could be crucial for primary prevention of major diseases.

Rotation project

This project will utilise pre-existing data collected in the age 46 biomedical assessment of the 1970 British Cohort Study. Physical behaviours were collected in ~5,000 participants using a thigh mounted accelerometer device (activPAL 3 micro) worn continuously for 7 days. Various biomedical data were also collected including biomarkers, adiposity, and blood pressure, together with medical history. The aim of this project is to identify individual clusters or patterns of physical behaviours using sophisticated modelling techniques (e.g., K-mean Cluster). We will further examine how such patterns in behaviours are associated with risk markers and health outcomes. The project will provide exposure to using large scale population data and epidemiological analyses. It would be advantageous for the student to have basic knowledge of statistical software packages such as SPSS, and an interest in using large scale data.


Hamer M, Stamatakis E, Chastin S, Pearson N, Brown M, Gilbert E, Sullivan A. Feasibility of Measuring Sedentary Time Using Data From a Thigh-Worn Accelerometer. Am J Epidemiol. 2020 Sep 1;189(9):963-971. doi: 10.1093/aje/kwaa047.

Huang BH, Hamer M, Chastin S, Pearson N, Koster A, Stamatakis E. Cross-sectional associations of device-measured sedentary behaviour and physical activity with cardiometabolic health in the 1970 British Cohort Study. Diabet Med. 2021 Feb;38(2):e14392. doi: 10.1111/dme.14392.



Martin Pule

Position: Senior Lecturer Location: Cancer Institute Email contact: [email protected] Theme: Experimental and Personalized Medicine


I am director of the UCL Chimeric Antigen Receptor (CAR) programme based in the Cancer Institute. My work involves designing artificial proteins and genes which re-programme immune cells to recognize cancer. My laboratory is at the junction between therapeutics, immunology and synthetic biology.

https://www.ucl.ac.uk/cancer/research/ucl-car-t-programme

Rotation project Chimeric antigen receptor (CAR) T cells are revolu- tionizing the treatment of refractory malignancies. CAR T cell therapy is highly effective in some 40% patients with diffuse large B-cell lymphoma (DLBCL) with sustained responses. In the remainder, however CAR T cells fail to induce remission, or the remission is very transient. We are starting to understand why this happens – DLBCL tumours surround themselves with an inhibitory microenvironment. In particular, myeloid derived suppressor cells (MDSCs) act as a profound inhibitor of CAR T cell function through a number of different pathways. Simple strategies to deal with MDSCs are lacking. We have recently developed a new way of engineering T cells to release active chemotherapy only into the side of disease – we do this by engineering the CAR T cells to additionally express an enzyme which convers a pro-drug to an active drug (see figure). We believe this will create an area of “fall-out” around CAR T cells which in turn will be a highly effective way to deplete MDSCs. The rotation project will explore the mechanism of inhibition of MDSCs on CAR T cells and the effect of chemotherapeutic “fallout” on their presence and function.


Combining phage display with SMRTbell next-generation sequencing for the rapid discovery of functional scFv fragments. Nannini F, Senicar L, Parekh F, Kong KJ, Kinna A, Bughda R, Sillibourne J, Hu X, Ma B, Bai Y, Ferrari M, Pule MA, Onuoha SC. MAbs. 2021 Jan-Dec;13(1):1864084. PMID: 33382949

Antitumor activity without on-target off-tumor toxicity of GD2-chimeric antigen receptor T cells in patients with neuroblastoma. Straathof K, Flutter B ... Pule M, Anderson J. Sci Transl Med. 2020 Nov 25;12(571) PMID: 33239386

Enhanced CAR T cell expansion and prolonged persistence in pediatric patients with ALL treated with a low- affinity CD19 CAR. Ghorashian S, Kramer AM … Pule MA, Amrolia PJ. Nat Med. 2019 Sep;25(9):1408- 1414. doi: 10.1038/s41591-019-0549-5. Epub 2019 Sep 2. PMID: 31477906

Targeting the T cell receptor β-chain constant region for immunotherapy of T cell malignancies. Maciocia PM, Wawrzyniecka PA, Philip B, Ricciardelli I, Akarca AU, Onuoha SC, Legut M, Cole DK, Sewell AK, Gritti G, Somja J, Piris MA, Peggs KS, Linch DC, Marafioti T, Pule MA. Nat Med. 2017 Dec;23(12):1416-1423. doi: 10.1038/nm.4444. Epub 2017 Nov 13. PMID: 29131157


https://www.ucl.ac.uk/cancer/research/ucl-car-t-programme


Dr Matthew Reeves

Position: Associate Professor of Molecular Virology Location: Institute of Immunity & Transplantation Email contact: [email protected] Theme: Experimental and Personalised Medicine


Human cytomegalovirus (HCMV) is a leading cause of disease in neonates and transplant patients. Our research centres on a molecular and immunological understanding of the host:pathogen interaction in order to inform therapeutic strategies to treat HCMV. A key interest of our lab is the development of an effective HCMV vaccine.

Rotation project

Vaccination represents, arguably, the greatest achievement of modern medicine. Consequently, a

number of HCMV vaccines have been tested. Our laboratory has demonstrated that a vaccine based

on a single viral glycoprotein important for viral entry (called gB) provides the best protection in

transplant patients although this was restricted to 50% of patients. The objective now is to understand

why certain individuals were protected. Using epitope mapping we have identified and patented a novel

antibody response (AD6) in vaccine recipients that correlates with a reduction in viraemia in vivo.

Intriguingly, naturally infected individuals do not make a response to AD6 suggesting that this vaccine

induced response could represent an ‘achilles heel’ for the virus. Our preliminary data show that the

protective response is a non-neutralising antibody response. Thus the rotation and PhD project will

seek to understand the mechanistic basis of protection of the humoral response. A major question will

centre on trying to understand why AD6, and thus responses against it, are important for the biology of

HCMV. The goal is to provide the evidence base for a follow up phase II study of a novel HCMV vaccine

candidate. The project will place the student at the interface of bench science and clinical medicine

using in vitro assays to measure the impact of immune functions on viral replication and correlating this

with data from clinical studies in vivo.


5 Key references: (note Ilona Baraniak was a previous PhD student working on this project)

• Baraniak, I. ..... & Reeves M.B. (2019) Lancet EBioMedicine 50:45-54

• Baraniak I.…& Reeves M.B. (2019) J. Inf. Dis. 220(2):228-232

• Baraniak I …& Reeves M.B. (2018) PNAS 115(24):6273-6278

• Baraniak I.... Reeves M.B. (2018) J. Infect. Dis. 217(12):1907-17

• Baraniak I., Reeves M. & Griffiths P. (2018) Criteria to define interruption of transmission of

human cytomegalovirus from organ donor to recipient Rev. Med. Virol. 28(1): doi:

10.1002/rmv.1958 (review)



Dr Michelle Heys/ Prof Mario Cortina-Borja

Position: Associate Professor (M Heys) and Professor (Mario Cortina Borja) Location: GOSICH Research & Teaching Department Email contact: [email protected] Theme: EPM

Research overview: Optimisation of diagnostic algorithms for sick and vulnerable newborns in low resource settings.

Globally, 2.4 million newborns die per year, mostly in low-resource settings (LRS) hospitals. We have developed a learning healthcare system for newborn care LRS: Neotree (http://www.neotree.org/). You will analyse Neotree data to propose, validate and implement predictive models for diagnosis and management of neonatal sepsis and/or respiratory distress.

Rotation project Background: Clinical prediction models support timely, accurate diagnosis of neonatal sepsis and respiratory distress and optimise management in low-resource settings (LRS). The Neotree is a LRS digital quality improvement system for newborn care combining tablet-based data capture, clinical decision and management support, education in newborn care, data export, and linkage to analytics dashboards. We have co-developed this intervention with >350 healthcare professionals in two hospitals in Zimbabwe and one in Malawi. Data collection is ongoing with information from >13,000 newborns so far. Our Delphi study identified evidence gaps in neonatal guidelines included in the Neotree: sepsis, neonatal encephalopathy, respiratory distress and thermoregulation (Evans 2021). Further, we have developed a predictive model for newborn sepsis. (Neal 2020) Aim: To construct, validate and implement clinical prediction models to diagnose neonatal sepsis and respiratory distress without requiring laboratory tests or X-rays, using the routine clinical data collected by the Neotree app. Methods: You will develop classification and machine learning methods for prediction of newborn sepsis and respiratory distress. This project would suit a candidate with programming experience in R or Python who is either a quantitatively competent clinician or a biomedical statistician /data scientist with experience or understanding of clinical and medical data.

Figure: Sample screen shots of Neotree front end (App interface): Recorded observation, examination & data capture by the HCP triggers timely guidelines, education and management giving decision support. On completion,

Relevant publications: https://www.medrxiv.org/content/10.1101/2021.01.06.21249322v1;

DOI: 10.1136/bmjopen-2020-042124; doi: 10.1016/j.siny.2021.101204; doi: 10.1136/bmjoq-2020-001043; doi:

10.2196/16485; BMJ Open. 2020 Aug 20;10(8):e039712;

https://www.sciencedirect.com/science/article/pii/S259008892030010X; doi: 10.1136/archdischild-2018-316055; doi:10.1136/bmjopen-2019-034987. PMID: 32457078. doi: 10.1136/bmjopen-2018-027301. doi: 10.1136/bmjgh-

2018-000860. eCollection 2019. doi: 10.1136/archdischild-2017-313867. doi: 10.1136/archdischild-2017-313307; doi: 10.1186/s12913-017-2171-x PMID:28412944; doi: 10.2471/BLT.16.170803.


http://www.neotree.org/)

https://www.medrxiv.org/content/10.1101/2021.01.06.21249322v1

https://doi.org/10.1136/bmjopen-2020-042124

https://bmjopenquality.bmj.com/content/10/1/e001043.long

https://mhealth.jmir.org/2020/10/e16485

https://mhealth.jmir.org/2020/10/e16485

https://bmjopen.bmj.com/content/bmjopen/10/8/e039712.full.pdf

https://www.sciencedirect.com/science/article/pii/S259008892030010X

https://ep.bmj.com/content/105/5/296.long

https://bmjopen.bmj.com/content/10/5/e034987.long


Dr Mona Bajaj-Elliott

Position: Associate Professor Location: GOSICH Research & Teaching Department Email contact: [email protected] Theme: EPM


How do gut microbial changes influence clinical outcome in hematopoietic stem cell transplantation?

Microbes (‘microbiome’) that live in the digestive tract are key to health; a dysregulated microbiome contributes to many infectious, inflammatory, metabolic and neurological conditions. We hypothesise that “extensive antimicrobial usage during stem-cell transplantation has a detrimental impact on the microbiome resulting in adverse clinical outcomes post-transplantation”.

Rotation project

Background. We have longitudinal (pre- and post-transplant) faecal samples from paediatric patients undergoing allogeneic (matched donor) or autologous hematopoietic stem cell transplantation (HSCT) at Great Ormond Street Hospital. Although our previous work has identified significant changes in microbial structure and function in response to allo-HSCT (manuscript submitted), molecular information is lacking. The rotation project will involve:

Aim: To characterise changes in microbial taxa in ‘Pre- versus post-transplantation’ faecal samples using whole genome metagenomics.

Details: The samples will be prepared under the supervision of the UCL Pathogen Genomics Unit and whole genome shot gun metagenomic sequencing will be performed. Metagenomic analysis will be conducted under the supervision of Professor Balloux and Dr van Dorp (UCL Genetics Institute). Computational and statistical analysis will be performed to study the impact of medication on the gut microbiome ‘integrity’ and frequency of infectious episodes and graft ‘status’ post-transplantation (Professor Standing).

Conclusion: Information gained will allow us to extend our study to a larger cohort of patients.


Relevant publications: 1 Shaw L et al., 2019 ISME J 10.1038_s41396-019-0392-1; 2Shono Y et al., 2016.Sci Transl Med. 8:339



Dr Caroline Weight, Dr Andrea Gori & Professor Robert Heyderman, Position: Head of Department, Senior Research Fellow Location: Rayne Building, Bloomsbury Email contact: [email protected]; [email protected] [email protected] Theme: Experimental and Personalised Medicine


We study how bacteria colonise mucosal surfaces and manipulate host defences to promote their onward transmission. We interrogate these processes in cell culture systems and a human experimental infection model. We have shown that a common cause of pneumonia and meningitis, Streptococcus pneumoniae, triggers inflammation when it invades epithelial cells. We have also recently identified an unusual variant of S. pneumoniae that has escaped control by vaccines in Malawi, Africa.

Rotation project In this rotational project we will investigate the ability of this serotype 3 variant (ST700) to adhere and invade epithelial cells, and then trigger an inflammatory response. These processes will be assessed using confocal microscopy and host transcriptomics. Fluorescent probes will be used to characterise the molecules that form the intracellular vacuole and determine the fate of intracellular bacteria.

To better understand the relationship between genotype and phenotype, the findings from these experiments will then be compared with those in ongoing serotype 3 studies in the human experimental infection model. Alongside this wet-lab and human experimental medicine experience, there will be the opportunity to develop proficiency in the bioinformatic techniques necessary to perform genomic comparisons of a range of serotype 3 strains and phylogenetically close serotypes (such as 19F and 14), in order to understand the mechanisms that have enabled the ST700 strain to emerge.

Publications

Connor MG, Camarasa TMN, Patey E, et al. The histone demethylase KDM6B fine-tunes the host response to S. pneumoniae. Nature Microbiology Dec 21

Sugar-coated Killer: Serotype 3 pneumococcal disease. Luck JN, Tettelin H and Orihuela CJ. 2020. Frontiers in Cellular and Infection Microbiology: 10:613287

Jochems SP, de Ruiter K, Solorzano C et al. Innate and adaptive nasal mucosal immune responses following experimental human pneumococcal colonization. 2020. J Clin Invest. Jul 30;130. pii: 128865.

Weight CM, Venturini C, Pojar S, et al. Microinvasion by Streptococcus pneumoniae induces epithelial innate immunity during colonisation at the human mucosal surface. Nat Commun 2019; 10(1): 3060.

Ogawa M, Matsuda R, Takada N et al. Molecular mechanisms of Streptococcus pneumoniae-targeted autophagy via pneumolysin, golgi-resident Rab41 and Nedd4-1-mediated K63-linked ubiqitination. Cellular Microbiology 2018; 20:e12846

De Wals P. Commentary on paradoxical observations pertaining to the impact of the 13-valent pneumococcal conjugate vaccine on serotype 3 Streptococcus pneumoniae infections in children. Vaccine. 2018 Sep 5;36:5495-5496.

Sings HL, De Wals P, Gessner BD, Isturiz R, Laferriere C, McLaughlin JM, Pelton S, Schmitt HJ, Suaya JA, Jodar L. Effectiveness of 13-Valent Pneumococcal Conjugate Vaccine Against Invasive Disease Caused by Serotype 3 in Children: A Systematic Review and Meta-analysis of Observational Studies. Clin Infect Dis. 2019 May 30;68:2135-2143.

Azarian T, Mitchell PK, Georgieva M, Thompson CM, Ghouila A, Pollard AJ, von Gottberg A, du Plessis M, Antonio M, Kwambana-Adams BA, Clarke SC, Everett D, Cornick J, Sadowy E, Hryniewicz W, Skoczynska A, Moïsi JC, McGee L, Beall B, Metcalf BJ, Breiman RF, Ho PL, Reid R, O'Brien KL, Gladstone RA, Bentley SD, Hanage WP. Global emergence and population dynamics of divergent serotype 3 CC180 pneumococci. PLoS Pathog. 2018 Nov 26;14:e1007438.







NAME: Prof Stephen Pereira / Dr Pilar Acedo

Position: Professor of Hepatology & Gastroenterology / Senior Research Fellow Location: Royal Free Hospital Email contact: [email protected] [email protected] Theme: Experimental and Personalised Medicine


Our multidisciplinary team formed by basic and clinical scientists aims to improve the outcome of patients with pancreatic and biliary cancers by i) generating clinically relevant in vitro models mimicking human disease, ii) investigating novel diagnostic markers, and iii) developing more effective therapeutic strategies for these cancers

Rotation project

Pancreatic and bile duct cancers are amongst the deadliest cancers due to late diagnosis and lack of effective therapies. These cancers are characterised by an aggressive, invasive and migrative potential, which is regulated by the crosstalk between cancer and neighbouring cells. However, the exact mechanism regulating these processes is not fully understood yet.

A key issue in pancreaticobiliary cancer research is the lack of human models that recapitulate tumour complexity, organisation and physiology, compromising the translatability of preclinical results to the clinical setting. Thus, this project will focus on deciphering the key role of the tissue microenvironment in pancreaticobiliary cancers physiology and behaviour. The student will develop and characterise clinically relevant 3D patient-derived models containing cancer cells and stromal components (e.g. cancer associated fibroblasts, stellate cells, immune cells). We will decipher changes induced in cancer cells by this complex crosstalk at the transcriptome (e.g. RNAseq) and secretome (e.g. exosomes) levels. This will accelerate prognostic and diagnostic biomarker discovery, by identifying specific gene signatures while considering cell-to-cell interaction and paracrine crosstalk. This will also increase accuracy for the identification of novel therapeutic targets and potential markers associated with disease progression and aggressiveness of pancreaticobiliary cancers. We will build on our experience in biomarker discovery and organoid establishment to unravel cancer-specific and immuno-inflammatory markers differently expressed in these models.


1. Garcia-Sampedro A, Acedo P, Pereira SP. Established and Emerging Biomarkers for Prediction, Early Detection, and Prognostication of Cholangiocarcinoma. Springer, 2021.

2. Ney A. et al, Modelling Pancreatic Neuroendocrine Cancer: From Bench Side to Clinic. Cancers, 2020.

3. Pereira SP, et al. Early detection of pancreatic cancer. The Lancet Gastroenterology & Hepatology, 2020.

4. Marin JG et al. Current and novel therapeutic opportunities for systemic therapy in biliary cancer. British Journal of Cancer, 2020.




Dr Susan Heavy/ Dr. ir. Eirini Velliou

Position: Lecturer in Translational Medicine/ Associate Professor Location: Centre for 3D Models of Health and Disease Division of Surgery and Interventional Sciences, Charles Bell House Email contact: [email protected] Theme: Experimental and Personalised Medicine


This project will bring together two emerging methodologies to better develop individualised treatment options for cancer patients. 3D culture of cancer cells and patient tissue will be combined with spatial biology approaches, offering a cutting-edge platform for testing targeted therapies pre- clinically.

Rotation project This rotation project will involve investigation of 3D models of cancer, working towards personalised medicine approaches for treating the disease. Mixed cell populations will be treated with emerging targeted therapies, and analysed using spatial biology approaches. Spatial biology was the Nature method of the year in 2020, and is a rapidly evolving field, which allows researchers to visualise and quantify expression of RNA, proteins, metabolites or other molecules across their samples. The results offer a mixture of highly multiplexed imaging with next generation sequencing – so the researcher can visualise expression of thousands of genes and how they relate spatially to each other, across their samples. As cancer researchers develop ever more complex mixed cell 3D cultures, such as organoids, explants, and tumour-on-a-chip, it is crucial that we analyse the heterogeneity, microenvironment and architecture in the detail it deserves, and these emerging methodologies allow us to do this. The full PHD project, and the wider goal of our group is to develop personalised 3D models that we can use to determine which treatment an individual patient should be offered. This PhD project will help to reach this goal by mixing the two technology development sides of our work – improving 3D culture models, and optimising spatial biology approaches for assessing these.


A recent paper where we carried out pre-clinical investigations of some co-targeted therapies in prostate cancer in vitro and ex vivo: Luszczak, S., Simpson, B.S., Stopka-Farooqui, U. et al. Co-targeting PIM and PI3K/mTOR using multikinase inhibitor AUM302 and a combination of AZD-1208 and BEZ235 in prostate cancer. Sci Rep 10, 14380 (2020). https://doi.org/10.1038/s41598-020-71263-9

The MRI guided biobanking method that we used to collect human prostate tissue for this project: Heavey, S, Costa, H, Pye, H, et al. PEOPLE: PatiEnt prOstate samPLes for rEsearch, a tissue collection pathway utilizing magnetic resonance imaging data to target tumor and benign tissue in fresh radical prostatectomy specimens. The Prostate. 2019; 79: 768- 777. https://doi.org/10.1002/pros.23782

A review on some of the targeted therapies we are investigating in 3D models: Luszczak, S., Kumar, C., Sathyadevan, V.K. et al. PIM kinase inhibition: co-targeted therapeutic approaches in prostate cancer. Sig Transduct Target Ther 5, 7 (2020). https://doi.org/10.1038/s41392-020-0109-y

My full publications list: https://scholar.google.com/citations?user=TuCg6SAAAAAJ&hl=en


https://doi.org/10.1002/pros.23782


Alessia Cavazza

Position: Lecturer in Gene Therapy Location: GOSICH Research & Teaching Department Email contact: [email protected] Theme: Experimental and personalised medicine


Cavazza’s lab is dedicated to generating gene therapies for primary immunodeficiencies in children, many of whom cannot be cured by any existing therapies. Our research aims to cure these children by editing their own stem cells and reimplanting them, allowing them to develop healthy immune systems.

Rotation project

Development of a CRISPR/Cas9 gene editing platform to correct Severe Combined Immunodeficiency caused by mutations in the IL7RA gene

IL7R Severe combined immunodeficiency (SCID) is a genetic disorder caused by IL7R deficiency which leads to absence of T lymphocytes resulting in profound failure of the immune response, with severe and opportunistic infections leading to fatal outcome. While hematopoietic stem cell (HSC) transplantation is curative for all forms of SCID, incomplete immune reconstitution and toxicities can cause significant morbidities, meaning that alternative approaches are desirable. Gene therapy applied to IL7R SCID has shown that constitutive and unregulated expression of the gene predisposes to leukemia. Genome editing represents a promising alternative as it could correct the endogenous IL7R locus while avoiding issues of unregulated transgene expression. The goal of this project is to develop CRISPR/Cas9-based genome editing to functionally correct mutations in the IL7R genes in HSCs derived from SCID patients. Our preliminary results have shown that by delivering our optimized CRISPR/Cas9 reagents together with an AAV6 donor template we are able to efficiently knock-in a reporter cassette into the IL7R locus in up to 50% of HSCs. We now aim to move forward and restore IL7R expression in IL7R deficient cells from SCID patients, to establish a viable gene editing-based therapeutic approach to treat IL7R SCID.


1. Rai R., Thrasher AJ., Cavazza A. (2020). Gene editing for the treatment of Primary Immunodeficiencies. HUMAN GENE THERAPY, 2020 https://doi.org/10.1089/hum.2020.185

2. Rai, R., Romito, M., Rivers, E., Turchiano, G., Blattner, G., Vetharoy, W., ...Cavazza, A. (2020). Targeted gene correction of human hematopoietic stem cells for the treatment of Wiskott - Aldrich Syndrome. NATURE COMMUNICATIONS, 11 (1), doi:10.1038/s41467-020-17626-2

3. Jiang Q, Li WQ, Aiello FB, et al. Retroviral transduction of IL7Ralpha into IL7Ralpha-/- bone marrow progenitors: correction of lymphoid deficiency and induction of neutrophilia. Gene Ther 2005;12:1761-1768



Professor Vijay Chudasama Position: Professor (Organic Chemistry/Chemical Biology) Location: Kathleen Lonsdale Building (UCL Chemistry) Email contact: [email protected] Theme: Experimental and personalised medicine

Research overview (50 words or less) - The Chudasama Group is primarily focused on answering important biological questions through the application of Organic Chemistry. We do this by designing and tuning a variety of bespoke chemical tools (from chemoselective reagents with orthogonal “click” handles to photoswitchable azobenzenes) for the particular system we are studying.

Rotation project - Over the years, a wide variety of methods have been established for the selective modification of various amino acids on peptides/proteins, e.g. Cys, Lys, Tyr, Met.1 However, the absence of a reliable strategy for modification of the C-terminus has persisted; to the best of our knowledge, the only known method for C-terminal modification is that pioneered in 2017 by Macmillian et al.2 However this strategy is decarboxylative, uses an Ir photocatalyst, requires pH 3.5 for good yields and introduces a highly unnatural group onto the protein. Prima facie, the lack of methods for C-terminus modification seems logical as it is conceptually difficult to activate/react only one carboxylic acid in the presence of all others. In this rotation, we are proposing to develop a first-in-class method for the site-selective modification of C-terminal cysteines. This will enable site-selective conjugation of native antibodies as the vast majority of clinically relevant antibodies bear a C-terminal cysteine (leading to the various applications of antibody conjugates, e.g. for use in cancer imaging and therapy, diagnostics, immunotherapy,3-6 whilst also representing a fundamental addition to the toolbox of reactions in the broader field of protein bioconjugation). Our core concept is to utilise sulfur selective chemistries to deliver coupling reagents to the carboxylate on the C-terminus, which will then enable specific amide bond formation. Encouragingly, we have recently obtained a key preliminary result in that we have discovered something specific about C-terminal cysteines: After C-terminal cysteine 1 was oxidised using Ellman’s reagent to form disulfide 2, reaction with a phosphine resulted in the formation of thiophosphonium adduct 3, which could react to form an amide.7 This sets the groundwork for application on antibody scaffolds to construct antibody conjugates for use in therapy, imaging, etc.


1. Chem. Rev., 2015, 115, 2174-2195. 2. Nature Chem., 2017, 10, 205. 3. Nature Chem., 2016, 8, 114-119. 4. Nature Commun., 2015, 6, 6645. 5. Drug Disc. Today: Tech., 2018, 30, 105-109. 6. Drug Disc. Today: Tech., 2018, 30, 11-20. 7. Tetrahedron, 2005, 61, 10827-10852. Further, more recent, publications from the group can be found here: http://chudasama-group.eu/publications/

http://chudasama-group.eu/publications/


Stephen B Walsh Position: Associate Professor Experimental Medicine Location: UCL, Royal Free Campus Email contact: [email protected] Theme: Experimental and personalised medicine

Research overview (50 words or less) The drug treatment of hypertension is overwhelmingly uninformed by patient’s individual physiology We will use patient-specific urine and blood derived cells in an ‘organ-on-a-chip’ to predict patient responses to antihypertensive medication. The student will work on culturing endothelial cells from blood samples from patients with a rare inherited hypertensive disease. Rotation project Despite decades of study, much of the aetiology and pathophysiology of hypertension are unclear; however, kidney and endothelial interactions appear to be important. Furthermore, despite hypertension affecting >1 billion people worldwide, there are no tests to guide treatment, which is often poorly tolerated. New techniques allow the ex vivo assessment of patient specific kidney and endothelial tissue, including direct and safe pharmacological testing. The technology (‘organ-on-a-chip’ (OOAC)) consists of multi-channel chips arranged in plates plates that allow cells to be cultured into 3D tubular systems in contact with channels containing other cell types with extracellular matrix in between. Our lab can isolate and grow primary cells of specific renal tubular segment origin from a urine sample and culture these in an OOAC system. The next step is to isolate blood outgrowth endothelial cells (BOECs) from routine blood samples and to culture these in the same OOAC system. Many laboratories have managed to do this with successful and robust protocols 1–3. We plan to use this OOAC system to culture BOECs and renal tubular cells from patients with the rare monogenic blood pressure disease, Gordon syndrome, which recently was described to also have a vascular component to their hypertension. These patients (from the clinic of SBW, who has extensive experience of this and related blood pressure diseases4,5) are very sensitive to thiazide diuretics, a common antihypertensive, but the vascular effects are poorly documented. The student will:

• Develop existing protocols to culture BOECs from a 50ml blood sample from healthy volunteers and patients with Gordon syndrome from the clinic of SBW.

• Culture these cells in an OOAC system in a ‘vascular channel’ along with urine derived tubular cells from the same patient (this protocol is already running in our laboratory) in the corresponding ‘renal channel’.

• Cells in the OOAC will be identified with immunostains (e.g. anti-SLC12A3, anti-CD31) and imaged via confocal microscopy.

• The OOAC system, once working will then be cultured with thiazide diuretic or vehicle. The resulting chloride and potassium concentration in the renal channel and the NO concentration in the vascular channel will be measured as outputs.

Relevant publications 1. Ahmetaj-Shala, B. et al. A bioassay system of autologous human endothelial, smooth muscle cells, and

leukocytes for use in drug discovery, phenotyping, and tissue engineering. FASEB J. 34, 1745–1754 (2020).

2. Smadja, D. M. et al. Standardization of methods to quantify and culture endothelial colony-forming cells derived from peripheral blood. J. Thromb. Haemost. JTH 17, 1190–1194 (2019).

3. Martin-Ramirez, J., Hofman, M., van den Biggelaar, M., Hebbel, R. P. & Voorberg, J. Establishment of outgrowth endothelial cells from peripheral blood. Nat. Protoc. 7, 1709–1715 (2012).

4. Hoorn, E. J. et al. The calcineurin inhibitor tacrolimus activates the renal sodium chloride cotransporter to cause hypertension. Nat. Med. 17, 1304–1309 (2011).

5. Evans, R. D. R. et al. Inherited salt-losing tubulopathies are associated with immunodeficiency due to impaired IL-17 responses. Nat. Commun. 11, 4368 (2020).

ucl-birkbeck mrc dtp experimental and personalised

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