Phase IV, 2016-2020 :

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Phase IV, 2016-2020 :

Towards clinical proofs of concept validating our pharmacological and regenerative medicine approaches


The 4th strategic plan of I-Stem coincided with the migration of the Institute in brand new premises, offered to us by the Genopole within the framework of the CRCT (Clinical and Translational Research Center). We occupy 1600 square meters, half of which divided into 4 experimental zones of 200 square meters each, devoted respectively to the culture of human cells (L2 confined laboratories), to “dry” biology (biochemistry and molecular biology), robotic technologies of production and analysis, and support sectors (microscopy, cryopreservation, servers, etc …). The other half of the laboratory is occupied by offices (80 people), storage, and living and circulation areas. Access is, moreover, free to a large conference room of 200 square meters and several meeting rooms.

Development of cell therapy products

As regards regenerative medicine, the activities of I-Stem’s biological research teams can be grouped into three categories: completion of ongoing programs, innovation for improvement of ongoing programs, innovation for future programs.

First of all, of course, we are completing our current programs, that is to say in the period covered by this 4th strategic plan, until the complete technology transfer to the pharmaceutical establishment in charge of the production of ATMPs, and the implementation of clinical trials. In the absence of establishments with the requisite skills for the production of cells derived from pluripotent lines, we first went through an exploratory phase during which we tested several potential providers. Only Atlantic BioGMP (ABG), the contract manufacturing organisation of the EFS in Nantes, has fully met the specifications of STREAM and PACE. The close collaboration with EFS-ABG teams has already allowed us to submit a clinical trial application for the treatment of retinitis pigmentosa, which has been successful with an authorization delivered to us on January 23, 2019 by the regulatory authorities. The clinical trial itself, sponsored by CECS/I-Stem and supervised by the teams of the Clinical and Regulatory Management Department of the Institute of Biotherapy, will be carried out by our collaborators from the Institute of Vision and Health. Hospital XV-XX (Paris). The GMP production program is currently underway at EFS-ABG for the PACE (epidermis) program, for a clinical trial in collaboration with AP/HP teams in 2020.

The developed cell therapy products can also be modified to better meet the needs. We have launched this program of improvement on the epidermis. Because it is composed only of keratinocytes, the PACE leaflet does in fact reproduce this tissue imperfectly, let alone the entire skin coverage. Our work has led in recent years to the identification of differentiation protocols for complementary cell populations, melanocytes that pigment the skin and protect it against the genotoxic effect of UV, and fibroblasts that are the main element of the dermis and ensure, in particular, the interface with blood vessels. The “skin” cell therapy program at I-Stem will therefore be continued with a view to creating a more complete product, which will be pigmented and associated with a dermal sub-layer. This will enable us to initiate a “PACE 2” clinical program whose indications can be extended to a spectrum of pathologies beyond cutaneous sickle-cell ulcers.

We are looking to develop new cell products, this time derived not from ES cells but from iPS cells. For years I-Stem has been focusing on the complementary potential of cell therapy products derived from iPS cells, because the making of these lines can be done from selected donors. But cell therapy, like any biological transplant, faces the difficulty created by the immune system whose activity aims to reject any intrusion of biological material with an immune identity recognized as different from that of the recipient. A solution devised by British scientists fifteen years ago is to find particular donors in the general population who possess what is called a “triple-homozygous haplotype”, that is they only have one type of HLA-A antigen (the 2 A’s are identical), one type of HLA-B antigen and only one type of HLA-DR antigen. These donors should thus be compatible for heterozygotes with the same 3 markers and 3 others whose precise identity no longer has any consequence. We determined and published (in 2013) that the triple-homozygous donor alone with the most common haplotype in the Caucasian population (A1, B8, DR3: so it is A1A1, B8B8, DR3DR3) could serve up to 14.5 % of the population (heterozygotes A1Ax, B8By, DR3DRz) in France and in all countries of Caucasian population. We collaborate closely in the production of such iPS lines with AnneLise Bennaceur-Griscelli’s team in France, the Global Alliance for iPS Therapies (GAiT) worldwide.

There are several other ways of circumventing the immune system, which are grouped under the terms “ghost cells” (or “stealth cells”). The I-Stem teams are now exploring these avenues in close collaboration with Thierry Heidmann and his teams who have identified the molecular basis of such bypasses observed in physiological conditions (e.g. pregnancy) and have offered to put them to good use for regenerative medicine.

Pathology modeling and pharmacology programs

We are continuing programs undertaken during the third strategic plan, including Steinert’s myotonia and Duchenne muscular dystrophy (with a specific new program on the neurological impact of dystrophinopathies), spinal muscular atrophy, several limb girdle myopathies (program launched at the end of the 3rd plan), Wolfram syndrome, epidermolysis bullosa simplex, neurofibromatosis type 1 and Huntington’s disease. We refer readers who wish a detailed presentation of these research projects to the pages that specifically present them elsewhere on our site.

In parallel, through the MyoPharm program, we are now opening collaborations on several ultra-rare neuromuscular diseases (whose prevalence does not exceed a few hundred patients in France) around programs sponsored by other specialized institutes (GIPTIS, NeuroMyogene, Genethon, Institute of Myology, etc …). It seems to us technically possible today to systematically study the pathological mechanisms that accompany the mutations at the origin of any neuromuscular disease and to use these data to identify pharmacological compounds capable of oppose it. The scientific and technological underpinnings of such a program can be summarized, schematically, in a nutshell:

1. iPS cells can be derived from cells of any patient carrying a neuromuscular pathology.
2. Cell culture protocols make it possible to obtain motor neurons and myotubes, which are the most relevant in vitro models for studying neuromuscular diseases.
3. A technique (CRISPR/Cas) is used to modify the cell genome to create or correct a point mutation, making it possible to establish corrected control lines for the causal mutation of the pathology that is needed to identify by comparison the molecular and cellular abnormalities associated with the mutation.
4. High throughput sequencing (in its applications to gene expression analysis) allows the molecular functioning of mutated cells and controls to be compared and thus to identify molecular abnormalities.
5. High-content analytical platforms allow the systematic multi-parametric study of cellular and functional phenotypes arising from these molecular abnormalities.
6. High throughput screening tools are applicable to mutated cell populations, opening the way for the identification of repurposable drug candidates that can then be rapidly tracked -as a result of their repositioning- through the entire pathway to clinical trials.