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About Cooperation and Clusterization Involved in the Development of Rare Disease Drugs

Updated: Jul 18, 2022

A few weeks ago, Nature Medicine published the long-term follow-up results (median follow-up, 7.6 years) of phase I/II lentiviral vector-based gene therapy trials for eight patients with Wiskott-Aldrich syndrome (WAS). This 2022 publication marks a milestone in the development of this lentiviral vector-based gene therapy for a rare syndrome, and provides an interesting example of therapeutic innovation involving a private-public partnership. In presenting this brief overview of how these gene therapy trials were set up in France from 2010 onwards, the aim here is to focus on the type of cooperation and clusterization involved in the development of the therapy and the role played by the patient organization AFM-Telethon.

Gene therapy as an alternative to hematopoietic stem cell (HSC) transplantation

Wiskott-Aldrich syndrome is a rare and severe X-linked complex immune deficiency (estimated prevalence 1:250,000). The syndrome results in hemorrhages, severe and recurrent infections, critical eczema, and in some cases autoimmune reactions and the development of cancer. It is caused by mutations in the gene encoding the WAS protein (WASp) expressed in hematopoietic cells. The treatment of choice is allogeneic3 HLA-geno-identical hematopoietic stem cell (HSC) transplantation. The degree of HLA compatibility between donor and recipient is, with an early transplant (<5 years), one of the parameters which determines the efficiency of the transplant. HSC transplantation ensures a survival rate of about 80% (Fischer & Mahlaoui, 2013; Nau, 2015).

But in the absence of an HLA-compatible donor, what could be done? Gene therapy seemed to offer a solution: "transplanting the patient's own genetically modified hematopoietic stem cells" (Université Paris Cité, 2022). The first clinical trials started in 2010. Teams in Italy and Germany attempted retrovirus vector-based gene therapy. The clinical trials set up in France, sponsored by Genethon, are based on the lentiviral vector developed by Anne Galy's INTEGRARE team at Genethon. The lentiviral vector is used to introduce a healthy WAS gene into blood stem cells carrying the genetic anomaly (CD34+ hematopoietic stem cells) collected from patients, and thus to correct their own stem cells.

Locally maintained public-private collaborations

A first aspect of the clusterization process that can be highlighted is that to develop gene therapy (including this particular therapy), AFM-Telethon endeavored to develop collaborations with locally maintained public research institutions.

To better understand this case study, it is helpful to learn more about the sponsoring developer. Genethon is a nonprofit organization founded in 1990 by the AFM-Telethon, a French association of patients and parents of children with muscular dystrophy. The initial objective given to Genethon by AFM-Telethon was to provide research teams from various public or publicly funded research institutions with an unprecedented infrastructure (offering innovative equipment and staff) designed to map the human genome, track down the genes responsible for genetic diseases, and use this knowledge to develop innovative therapies. A particularity of the mapping project is that in 1993, in the midst of an international controversy over gene patenting, the first physical maps of the human genome produced in 1992 were handed over to UNESCO (United Nations Educational, Scientific and Cultural Organization) as a heritage to humanity (Rabeharisoa & Callon, 1999; Rabinow, 1999). Over the past 30 years, Genethon has developed expertise in the identification of genetic targets, the design and manufacturing of gene therapy products, and their pre-clinical and clinical development.

Genethon is located on the site of the Genopole. Genopole is a biocluster created in 1998 by the AFM-Telethon as a nonprofit organization, which became a public interest group (GIP) in 2002. The legal status of a GIP allows public and private partners to pool resources for implementing missions of general interest. Genople brings together the French government, local authorities, the University of Evry Val d'Essonne and biotechnology companies. Its mission is to develop research in genomics and life sciences, to become a teaching centre on these subject matters, to ensure the scientific coordination of the biocluster, and to promote the development of biotechnologies by creating, supporting, and hosting innovative companies.

The lentiviral vector-based gene therapy trials for patients with Wiskott-Aldrich syndrome is based on research led by the "novel molecular approaches in hematopoiesis and stem cell research" team set up in 2002 by Anne Galy, a biotech specialist, through an ATIGE grant from Genopole. The ATIGE grants (Thematic Incentive Actions of Genopole) were set up in 2001 to help future scientific leaders emerge by offering tenured researchers the opportunity to set up a team within a research unit already located in the biocluster. A few years later, in 2010, Anne Galy became the director of a newly created research unit named INTEGRARE - Integrated Genetic Approaches in Therapeutic Discovery for rare diseases. INTEGRARE is the joint research unit (UMR951) of three public research institutions - Inserm (French National Institute of Health and Medical Research), the University of Evry Val d'Essonne and the EPHE (École Pratique des Hautes Etudes) – as well as Genethon, where it is currently based. The vector-drug batches used for the trials launched in 2010 were “produced, controlled and released according to GMP standards by Genethon” (AFM-Telethon & Genethon, press release, 24 February 2010)

Launching clinical trials: rare diseases require international collaboration

A second aspect of the clusterization process is that the launch of this clinical trial allows researchers to observe the international collaborations required for the development of therapies for rare diseases. As stated by Fulvio Mavilio, Genethon's Scientific Director in 2015, when the first results of the trial were published (Hacein-Bey Abina, Gaspar &, Blondeau, 2015), "for very rare diseases such as Wiskott-Aldrich syndrome, multicenter clinical trials are the only way to prove the safety and efficacy of gene therapy and make the treatment available to all patients. We are following the same approach for other rare and not-so-rare blood diseases" (Inserm, 2015). Genethon is the sponsor of the trials launched in France at the Necker-Enfants Malades Hospital in Paris, and the Great Ormond Street Hospital in London, UK. Genethon also supplied the batches of vector-drugs used for the same trial conducted in the United States, anticipating at that time that the trial would include fifteen patients, five per site, who would be treated by 2013-2014 (AFM-Genethon, 21 July 2011).

An emphasis on a skills development process

For the AFM and the Genethon management teams, the search for an alternative treatment for Wiskott-Aldrich syndrome included the development of the skills needed to develop innovative drugs and set up clinical trials for rare diseases globally. According to Frédéric Revah, Chief Executive Officer of Genethon, "these initial results of our therapeutic trial for the treatment of Wiskott-Aldrich syndrome are very encouraging. They also illustrate the capacity of Genethon's teams to conduct not only upstream research to design treatments for these rare and complex diseases, but also to set up international clinical trials, to produce these advanced therapy drugs, to work with international teams and to control the regulatory aspects related to these trials in France and abroad. We are using these skills in other international gene therapy trials for rare genetic diseases of the immune system, blood, muscle, vision or liver.... We will continue the current trial with the goal of making the treatment available to patients" (Inserm, 2015).

Partnerships with the pharmaceutical industry

The French SPIN team is currently conducting case studies on several gene therapies supported by the AFM-Telethon, and with clinical trials sponsored by Genethon, which bring an additional dimension. Not only do the drug development and clinical trials involve the same configuration of public-private collaboration and international collaborations with hospital structures in Europe and the United States, but they also involve partnerships with the pharmaceutical industry. This complex configuration opens a series of important questions about innovative collaborations in response to unmet medical needs in rare disease care.



AFM-Genethon (24 February 2010). Press release. Thérapie génique des maladies rares. Généthon reçoit le feu vert pour un nouvel essai clinique concernant un déficit immunitaire sévère [Gene therapy for rare diseases. Genethon gets the green light for a new clinical trial for severe immune deficiency].

AFM-Genethon (21 July 2011). Press release. Généthon et le Children’s Hospital de Boston obtiennent l’autorisation de la FDA pour le démarrage d’un essai de thérapie génique pour le syndrome de Wiskott-Aldrich (WAS) [Genethon and the Boston Children's Hospital get FDA approval to start a gene therapy trial for Wiskott-Aldrich syndrome (WAS)].

Hacein-Bey Abina S, Gaspar HB, Blondeau J, . (2015). Outcome following gene therapy in patients with severe Wiskott-Aldrich syndrome. JAMA, 313, 1550–63.

Inserm (21 avril 2015). Nouveau succès de thérapie génique pour une maladie rare du système immunitaire : le syndrome de Wiskott-Aldrich. Communiqué. Inserm Service de Presse

Magnani Alessandra, Semeraro Michaela, Cavazzana Marina et al. (2022). Long-term safety and efficacy of lentiviral hematopoietic stem/progenitor cell gene therapy for Wiskott–Aldrich syndrome. Nature Medicine, 28, 71–80.

Nau Jean-Yves (2015). Syndrome de Wiskott-Aldrich : une nouvelle avancée de la thérapie génique. Revue Médicale Suisse, 472.

Fischer Alain & Mahlaoui Nizar(Last update: December 2013). Wiskott-Aldrich syndrome. Orphanet.

Rabehisora Vololona and Callon Michel (1999). Le pouvoir des malades. L'association française contre les myopathies et la recherche [The power of patients. The French Association against myopathies and Research]. Paris, Les presses de l'Ecole des Mines.

Rabinow Paul (1999). French DNA: Trouble in Purgatory. Chicago, University of Chicago Press.

Université Paris Cité (2O22). Press release "[Thérapie génique] Syndrome de Wiskott-Aldrich : transplantation chez le patient de ses propres cellules souches hématopoïétiques génétiquement modifiées". ["[Gene therapy] Wiskott-Aldrich syndrome: transplanting the patient's own genetically modified hematopoietic stem cells"]. Accessed May 24, 2022.

Illustration: Build upon Mario Klingemann’s “324 Blank Pages”, 2015 (CC BY-NC 2.0).


Written by: Florence Paterson

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