WP coordinator(s): A.Bachoud Levi (Node 3) – & A. Perrier (Node 5)
WPs collaborators: E. Brouillet (Node 1) , S. Palfi and P. Remy (Node 3), N. Cartier (Node 4)
Objectives and perimeter:
Intra-cerebral transplant can provide some functional benefit to patients suffering from neurological disorders in particular when neurodegeneration is localised and affects a limited number of neuronal subtypes as it is the case for patients suffering from Parkinson’s or Huntington’s disease. Homotypic neural progenitors derived from human pluripotent (embryonic or reprogrammed) stem cells are the therapeutic alternative to foetal tissues which suffer from insurmountable logistical hurdle as revealed in ongoing and published clinical trials. Predictive factors of transplant success in patients remain elusive and need to be identified urgently before stem cell therapy can be applied more broadly. WP1 objective is to develop new methodologies to foster the translation of successful experimental cell therapies for neurological disorders to the clinic and to determine how to improve this therapeutics in patients. Specific aims of WP1 will focus on methodological developments related to: 1) At the pre-clinical level: the conversion and Quality Control of research-grade stem cell derived grafting material into a clinical-grade product both in vitro and in vivo, 2) At the clinical level: neurological, immunological, data processing, regulatory and ethical issues specific to phase I/II clinical trials based on multi- or pluripotent stem cell derivatives.
State of the art:
Over the past decade, clinical trials have provided evidence of the benefit of foetal neural transplantation in neurodegenerative diseases in particular in Huntington’s disease (HD). For this devastating genetic disorder, that causes neuronal degeneration especially severe in the striatum, the surgical approach is the only therapeutic strategy that has so far demonstrated long-lasting improvements in patients. Building on this fact, “Multicentric Intracrebral Grafting in Huntington‘s disease” is the most ambitious program currently conducted in this domain (PI: Dr AC Bachoud-Lévi – Node 3). In brief, MIG-HD has already enrolled 46 transplanted patients in various centres in France and Belgium with a mean follow-up duration of 5 years. Because two patients remain to be transplanted, the efficacy results of the procedure are still unknown. Nevertheless, MIG-HD has already allowed to demonstrate the feasibility and relative efficacy of these cell transplantation approaches, paving the way for new cell-based therapeutic strategies for this and other brain diseases. However, it has also unravelled some of the difficulties and calls for adjustment of the procedure that need to be addressed for future trials. In parallel, Dr A Perrier’s group (Node 5) has during the past 6 years explored the potential of human pluripotent stem cells (hPSCs) to generate striatal grafts, assessing their therapeutic potential both in vitro and in small and large animal models of HD as well as the safety issues raised by the use of hPSC 1-3.