SC4HD comprises a group of clinicians and scientists actively involved in the development of cell therapy for Huntington's disease. The consortium co-opts expertise as required to facilitate progress, as well as invites outside views to ensure the scientific validity and rigour of statements issues by the group. It aims to provide guidelines with minimum criteria that should be accomplished prior to moving forward, and will generate a robust clinical development plan. The group is guided by a policy of open sharing of data, protocols and reagents, and participates in regular meetings. Patient input regarding stem cell based therapies in the context of other clinical trials and drugs are an important component of this effort.
Huntington’s disease (HD) is an inherited autosomal dominant neurodegenerative condition caused by a CAG repeat in the huntingtin gene on chromosome 4. Onset is variable, but most commonly in mid-life, resulting in slowly progressive deterioration of motor, cognitive and behavioural functions, in addition to a range of currently less well defined symptoms. Disease progresses over a period of 1-3 decades, with most sufferers eventually requiring help with all activities of daily living. Although some aspects of HD, notably there are some approved therapies for the chorea and a subset of the behavioural symptoms such as depression and anxiety, may respond to a variable extent to existing conventional treatments, most symptoms are not treatable and there are no disease-modifying treatments currently available.
The gene mutation in HD is known to lead to progressive neural dysfunction and neural degeneration, with striatal degeneration being an early obvious (but not exclusive) consequence. Most experimental cell therapy research to date has focused on the striatum with the aim being either to replace the striatal cells lost to the disease process in order to effect circuit repair and/or to support the survival of the remaining striatal cells, although targeting of other brain regions is not precluded. To date, transplantation of a variety of cells into both excitotoxic and genetic rodent models of HD and into large animal models of excitotixicity have supported the notion that cells can survive transplantation into the brain for extended periods of time and can lead to improved function. Transplantation of human fetal striatal cells has also demonstrated long term graft survival and some proof of concept that transplanted cells may lead to improved function, although the conditions for achieving this on a consistent basis are not yet defined. Thus, the cell therapy field for HD is still at an early experimental phase.
However, given the existence of early translational studies for human fetal cell transplantation in HD, the publication of several protocols for striatal progenitor differentiation from pluripotent stem cells, and published preclinical efficacy in using neural precursor cells for transplantation, SC4HD considers important to propose guidance for the establishment of first-in-human stem cell product transplantation studies for HD. In particular this will involve defining minimum criteria considered necessary by the consortium to proceed to clinical trials in a safe and ethical manner. Developing these criteria will involve consideration of all the elements required to undertake such trials in HD.
SC4HD will propose and publish guidance for development of a neural intra-cerebral stem cell-based therapy for HD.
The goals of the consortium are the following:
1. Share information and discuss common challenges.
2. Propose and publish guidelines for preclinical testing, clinical development and delivery of cell therapies to the brain for treatment of HD, including neuroprotection, circuit restoration or a combination of the two.
3. Keep abreast of competitive approaches to reappraise the likely and appropriate place for cell therapies in the treatment of HD.
4. Convene regular meetings with constituents and others with relevant expertise, including patients or patient advocates.
our STEERING COMMITEE
Dr. Romina Aron Badin
Dr Aron Badin joined the CEA in France for a 2 year post-doc investigating the antidyskinetic effects of a novel compound in parkinsonian primates. She was recruited permanently in the CEA and has directed both the primate Neurosurgery and Behavioural platforms in the Molecular Imaging research Center (MIRCen) since then. She was recently appointed deputy director of MIRCen and delegated director for the CEA at the Graduate School of Life Sciences and Health of Paris-Saclay University. She has been PI of over 30 projects involving non-human primates funded through national and international academic partners and industry, and has extensive expertise in the design and execution of pre-clinical protocols for brain delivery of drugs, viral vectors and cells, as well as in the assessment of cognitive and motor functions in macaques. She has been a consultant for the MJFF and an expert in the SCHEER scientific committee commissioned by the EU in 2017. She is part of the steering committee of the GDR BioSimia that federates all primate laboratories in France and of the French Basal Ganglia Club.
Dr. Gerhard Bauer
University of California, Davis
Gerhard Bauer is the Director of a GMP Facility. Professor of Hematology / Oncology.
Editor in Chief – Molecular Therapy – Methods and Clinical Development
University of California Davis. Institute For Regenerative Cures (IRC)
Monica Busse is a trials methodologist with active involvement in a programme of research dedicated to cell replacement therapies in Huntington’s Disease and Director for Mind, Brain, Neuroscience Trials in the Centre for Trials Research (CTR) at Cardiff University. Her expertise in functional and clinical assessment and the use of sensors to assess community level activity and inform clinical signal detection is applied in trials in rare diseases (primarily Huntington’s Disease but more recently extending to a range of rare neurological diseases) all of which utilise relatively novel designs including trials within cohorts.
Dr. Monica Busse
Professor Canals is the Director of Creatio, the Production and Validation Center of Advanced Therapies of the University of Barcelona. It comprises the Laboratory of Stem Cells and Regenerative Medicine performing both basic and translational research on the use of stem cells as an approach to understand and cure neurodegenerative diseases -mainly focusing on Huntington's and Parkinson's disease-, as well as a facility that provides ATMP-based solutions under GMP conditions. It is a technologically specialized center of execellence with an experienced multidisciplinary team which has great experience in advanced therapies. Dr. Canals has access to protocols and clinical applications related to stem cells, pre-clinical development of ATMPs, toxicology and drug screening platforms based on human cells, including pluripotent stem cells and human somatic stem cells isolation, characterization and expansion, and feasibility studies, IP management and technology transfer.
Dr. Josep M. Canals
University of Barcelona
Dr. Steven Goldman
University of Copenhagen
Steve Goldman is Professor of Neuroscience and Neurology at both the University of Copenhagen and the University of Rochester Medical Center (US). He is Co-Director of the Center for Translational Neuromedicine, which is based at both institutions. In Rochester, he is an attending physician in its neurology department, of which he is a former chairman. Goldman trained at the University of Pennsylvania (BA), Rockefeller University (PhD), and Cornell (MD), prior to his residency in neurology at New York Hospital-Cornell and the Memorial Sloan-Kettering Cancer Center. Goldman is interested in cell genesis and regeneration in the adult brain, with a focus on the use of stem and progenitor cells in both modeling and treating neurodegenerative and myelin diseases, including Huntington Disease. Goldman has published over 250 papers in his field, including over 30 US patents. He is a recipient of the Jacob Javits Neuroscience Award of the NIH and the Novo Nordisk Foundation Laureate Award. He has served as a permanent member of the FDA Cell, Tissue and Gene Therapy Advisory Committee, and is a co-founder of Oscine Corporation, a cell therapy company. His current work is supported by the NIMH, NINDS, Adelson Medical Research Foundation and Oscine in the US, and by the Olav Thon, Lundbeck and Novo Nordisk Foundations in Denmark.ente fuente para títulos, párrafos y más.
Dr. William Gray
Professor Gray is a neural stem cell clinician scientist studying brain repair and clinically active neurosurgeon specialising in epilepsy surgery and transplantation. His main interests are in the control of endogenous adult neural stem cells (adult hippocampal neurogenesis) and the effects of neuroinflammation on both endogenous and transplanted neural stem cells for brain repair. He has a specialist expertise in human neural culture of adult brain tissue resected at neurosurgery. He has a translational research programme spanning human cell biology and signalling, behavioural and imaging studies in humans, devices for drug and cell delivery to human brain and currently runs a clinical trial of Neural Transplantation in Huntington’s Disease with Professor Anne Rosser.
Anselme L. Perrier is a research director at the French National Institute of Health and Medical Research (Inserm) and group leader at the CEA/CNRS/Paris Saclay UMR9199 lab at Mircen (Fontenay-aux-Roses, France). A.L Perrier graduated from the Ecole Normale Supérieure de Lyon and earned his doctoral degree in Neuropharmacology in 2001 at the University Pierre & Marie Curie in Paris. A.L.P. trained as a postdoc in Dr L. Studer’s lab at the Sloan Kettering Institute. A.L.P is a neurobiologist with strong expertise in human pluripotent stem cells (hPSC) and Huntington’s disease. Over the years, he established novel strategies to produce specific neuronal cell populations from hPSCs and use them for disease modelling, drug discovery and to develop cell therapy approach for Huntington’s disease.
Dr. Anselme L. Perrier
CEA-MIRCen & Inserm
Dr. Anne Rosser
Professor Rosser is a Neuroscientist and Honorary Consultant Neurologist with a special interest in neurodegeneration, in particular Huntington’s Disease with which she has been involved since 1994. She is current Chair of the European Huntington’s Disease Network. She directs the Cardiff University Brain Repair Group, where the key focus is on repair and regeneration in neurodegenerative conditions such as Huntington’s and Parkinson’s diseases, and led the FP7 Consortium Repair-HD which addressed a range of preclinical and clinical questions important in translating stem cell therapies for Huntington’s disease. Along with Professors Gray and Busse, she runs an ongoing clinical trial of fetal cell neural Transplantation in Huntington’s Disease (TRIDENT).
Discoveries in human genetics have allowed investigators to make significant progress in understanding the underlying cellular mechanisms that are disrupted by these mutations and to develop rational therapeutics. The research in the Thompson lab has largely focused on understanding pathogenic mechanisms for neurodegenerative disease and FGFR3-associated cancers in order to identify and validate novel therapeutic targets for treatment of these diseases.
University of California, Irvine
Dr. Leslie M. Thompson
Vicki Wheelock is a Health Sciences Clinical Professor of Neurology and founding director of the HDSA Center of Excellence at University of California Davis Health. Dr. Wheelock has been a member of the Huntington Study Group since 1997 and has over 20 years’ experience as an investigator in Huntington disease clinical research studies. She formed a collaboration with UC Davis Institute for Regenerative Cures director Dr. Jan Nolta resulting in a grant funded by the California Institute for Regenerative Medicine (CIRM) to study mesenchymal stem cells overexpressing brain derived nerve growth factor as a potential therapeutic for HD. Dr. Wheelock serves as a clinical consultant for Dr. Leslie Thompson’s CIRM grant designed to develop human neural stem cells as a potential therapeutic for Huntington’s disease.
Dr. Vicki Wheelock
University of California, Davis