La production de cellules souches pour le traitement des maladies humaines, initiée dans les laboratoires de recherche, est en voie d’être reprise par l’industrie pharmaceutique dont l’objectif est de développer des médicaments de thérapie innovante (MTI) dépourvus d’effets néfastes, homogènes, reproductibles, en quantité suffisante et de coût raisonnable. L’utilisation thérapeutique des cellules souches a débuté avec les cellules souches hématopoïétiques humaines (HSC), médullaires et du sang du cordon, dans le traitement des aplasies, des leucémies et des maladies génétiques hématologiques. Elle s’est développée avec les cellules souches mésenchymateuses (MSC) produites en faible quantité par la moelle, mais aussi d’autres tissus, utilisées après isolement et culture. Des succès thérapeutiques ont été obtenus dans diverses affections cardiaques et cutanées grâce à leurs propriétés sécrétoires paracrines de facteurs de croissance. Un grand pas a été effectué avec l’usage des cellules souches pluripotentes embryonnaires (ESC) ou induites (iPS).

Les premières du fait des limites apportées par les lois de bioéthique et des risques de cancérogenèse ont été utilisées uniquement de façon isolée après différenciation, soit dans un but thérapeutique, soit dans le criblage in vitro de médicaments. Les iPS sont produites à partir de cellules adultes après reprogrammation et différenciation, puis utilisées à titre autologue chez le donneur, lui-même, ou allogénique chez d’autres sujets, la 2^econdition permettant seule une production de masse. Le passage à la phase industrielle de la production nécessite d’utiliser un équipement adéquat (bioréacteurs) et de respecter les bonnes pratiques de fabrication lors des phases finales de préparation. Le marché mondial croît chaque année surtout pour le traitement des maladies chroniques répandues (dégénérescence maculaire, arthrose, nécrose cardiaque, ulcères diabétiques…). La France dispose d’une dizaine de sociétés impliquées dans la préparation de ces MTI, et quelques essais thérapeutiques encore limités aux phases I et I/II ont été réalisés. Pour faciliter le développement de start-ups, quelques pays ont encouragé des approches partenariales entre les différents acteurs impliqués en montant des plateformes public-privé. La propriété intellectuelle des procédés est assurée par la prise de brevet qui reste impossible pour les cellules mêmes. Les résultats des essais thérapeutiques, même non concluants, devraient être accessibles sur un site ouvert à tous. Les contraintes règlementaires relatives aux MTI et aux MTI préparés ponctuellement relèvent de directives européennes après leur transcription dans la législation Française. La fabrication des MTI obéit aux bonnes pratiques définies par la règlementation. Leur évaluation avant leur mise sur le marché dépend de l’Agence Européenne des médicaments. Les deux Académies recommandent l’assouplissement de la réglementation et l’accélération des procédures afin de faciliter la production de MTI à base de cellules souches ainsi que diverses mesures destinées à aider à la création de start-ups spécialisées, en particulier la mise en place de centres de recherche collaborative pour les accompagner dans les domaines techniques et règlementaires.

The production of stem cells for the treatment of human diseases, initiated in research laboratories and in university hospitals, is developing in startups and is being taken over by the pharmaceutical industry with the aim of developing innovative therapeutic medicines (ITMs) that are homogeneous, reproducible, effective, reasonably priced and in sufficient amount to perform therapeutic trials.

The initial resource of human stem cells is free according to the ethical principle depriving the human body of any financial value. As regards biotechnologies, “ bio ” remains free, while “ technologies” are innovative practices in the industrial and commercial field. Therapeutic use of stem cells started with multipotent stem cells, mainly human hematopoietic stem cells (HSC) that are found in bone marrow, cord blood and placenta. These stem cells are utilized for allogeneic transplantation in aplasia, leukemia and hematologic genetic diseases. Bone marrow stem cells come from volunteer donors listed in a registry under the control of the French “ Agence Française de la Biomédecine ” (Biomedicine Agency, BMA). The autologous grafts for the treatment of genetic diseases consist in correcting the mutation in vitro and then reinjecting the cells to the patient. Mesenchymal stem cells (MSC), also multipotent, are present in very small quantities in the bone marrow and the cord, but also in other tissues, and are used after isolation and culture to multiply them. They are not very immunogenic. Therapeutic successes have been obtained in various cardiac and cutaneous affections through their paracrine secretory properties of growth factors rather than by the colonization of the injured tissues. A big step has been made with the use of embryonic (ESC) or induced pluripotent (iPS) stem cells. The use of the first obtained by culture of cells of embryo blastocysts is governed by the French laws of bioethics and requires the authorization of the BMA. ESCs are differentiated by appropriate medium culture in most mature cell varieties. Not very immunogenic, but potentially carcinogenic, they have been used only in therapeutic trials limited to a small number of patients with myocardial infarction or age-related macular degeneration. ESCs are also, after introduction of mutations, a modeling tool for genetic diseases and thus are used for the in vitro screening of drugs. IPS are produced from adult cells after reprogramming into stem cells and then differentiating into mature cells from all tissues. They can be used in an autologous fashion in genetic diseases after correction of the mutation in the donor cells and reinjection. Because of their unlimited production capacity and the absence of ethical questioning, they represent the material of the industrial manufacture of stem cells for therapeutic use despite the “ double disadvantage ” of being genetically unstable and immunogenic. They are therefore widely used in regenerative therapy trials, particularly in age-related macular degeneration. Their in vitro uses are numerous: modeling of human diseases from patients’ skin cells and obtaining of control cells by correction of the mutation in order to screen drugs, creation of 3-dimensional organoids as a new route to organ transplantation, generation of red blood cells very useful in alloimmunized patients or carriers of a rare phenotype.

The work initiated in the hospitals and in the academic research laboratories has developed in startups often created by researchers benefiting from the possibility opened by the French Law N ° 99-587 of July 12, 1999 which allows them the temporary passage to a private activity. Industrial production of the most promising products is the next step. It is restricted to the pharmaceutical industry, the blood transfusion establishments and the hospitals that have created an economic interest group and requires the authorization of the “ Agence nationale de la sécurité du médicament et des produits de santé ” (National Agency for the Safety of Medicines, NASM). The conditions to be fulfilled in order to proceed to the industrial stage are numerous:

Small organizations facing these difficulties may use public or private multi-partnership platforms such as, in France, “ Cell for cure ” set up by LFB, a state-owned company, and Ypo-Skesi created by I-Stem (AFM-Telethon). These platforms can select patients, reprogram and immortalize iPS, produce isogenic control lines, create differentiated cell banks, all available on catalog, and provide advice on the preparation of regulatory files.

The development of stem cells for therapeutic use in our country is based on one hundred academic teams, a dozen startups, and to a lesser extent on the pharmaceutical industry still at the planning stage. Only the L’Oreal group is actively working in the field of skin stem cells, mainly with the Episkin company that it has created. ITMs obtained in France have been the subject of a limited number of therapeutic trials up to phase II / III, each trial involving about thirty patients. The situation in other countries highlights our backwardness. Ten “ stem cell ” products are currently on the market, including none in France and around 20 tissue engineering products, two of which are marketed in France but not reimbursed by the Health Insurance. Note that to date are registered inclinicaltrials.gov142 clinical trials using MSC in the United States, 147 in Europe and 230 in China. The market in the world is changing rapidly. Of $ 8.5 billion in 2016, it is expected to reach more than $ 60 billion in 2020.

Stem cell production and research in the field raise ethical issues that the International Society for stem cell research has tried to answer. In addition to the questions posed by the use of ESC submitted in France to the regulation of the latest bioethics law, other directives concern the industrial phase, including the obligation to declare all therapeutic trials, convincing or not, in a register searchable by all and the demand for scientists and the media to present complete reports of trials including failures and complications.

Law N ° 2011-302 introduces into the Public Health Code a new type of product, the ITM. In fact, there are four types of usable products, each within a specific regulatory framework:

The use of these products is subject to a set of European and French regulatory texts. We will only mention the main ones. The European Union has confirmed the drug status with its inherent obligations for ITMs (N° 1394/2007). Directive N° 2004/23 / EC sets quality and safety standards at the different stages of ITM preparation. French law has introduced European directives into national legislation and has supplemented them, often making them even more restrictive. Thus, Law N^o2011-302 introduced the ITM in the Public Health Code (CSP) and decrees N^o2012/136 and 2016/1536 completed the Law. France has enacted the laws of bioethics, of which the last of August 6, 2013 amending the law No. 2011-814 regulates the use of ESC.

The creator of an ITM must, in accordance with this regulation, go through 3 steps to introduce it on the market and obtain its reimbursement. The first is the authorization to launch therapeutic trials that follows a national process. A double authorization is necessary. It is given independently by 2 bodies, the “ Comité de protection des personnes ” (Committee for the Protection of Persons, CPP) suitable for Biomedical Research and the NASM. The first verifies that all the requirements of the Law on the Protection of these persons, including the informed consent of the subjects, have been respected. The second takes the opinion of the BMA and, in case of genetic manipulation, of the “ Haut conseil des biotechnologies ” (High Council of Biotechnology). It also uses external experts. The final decision is known after about 6 months. The second stage of marketing authorization depends on the European Medicines Agency, which takes advice from the Committee for Advanced Therapies. With regard to reimbursement, we return to a national process that falls under the “ Commission de la transparence de la Haute Autorité de Santé, HAS (Transparency Commission of the High Health Authority). The latter takes the opinion of the “ Union nationale des caisses d’assurance maladie “(National Union of Health Insurance Funds) and the “ Comité économique des produits de santé ” (Economic Committee of Health Products), then decides on the price and the rate of care.

At the end of this report, the two academies formulate a series of recommendations concerning the legislation and the support of startups.