Severe Combined Immunodeficiency (SCID) is a rare genetic disease, resulting in a severe drop in the number of T and B lymphocytes and sometimes NK cells, the lymphocytes of the innate immune system. The result is severe, recurrent infectious complications, beginning in the first few months of life, associated with diarrhea or stunted growth, which can be life-threatening.
There are several types of SCID, depending on which genes are mutated. Treatment involves sterile isolation, immunoglobulins and antibiotics. The only curative treatment to date is hematopoietic stem cell allograft for patients with a compatible donor. For the others, gene therapy represents a therapeutic option, but for most DICS, it remains limited to clinical research protocols, or even unproven.
The first successes of gene therapy in humans were achieved in clinical trials to treat patients with SCID. Although these early trials demonstrated the feasibility and efficacy of the approach, they also revealed the genotoxic potential of certain gene therapy vectors. Technologies must therefore be improved.
Genethon teams have been working with a number of collaborators on the development of new, safe gene therapy treatments for two types of SCID, X-linked SCID and radiosensitive SCID.
Severe combined immunodeficiency linked to the X chromosome (SCID-X1): development of a lentiviral gene therapy by Genethon
SCID-X1 mainly affects boys who, if left untreated, usually die around the age of 1 year. DICS is caused by an anomaly of the IL2RG gene encoding the gamma chain common to several interleukin receptors that are growth factors for T, B and NK lymphocytes The incidence of this disease is around 1/200,000 births.
The first SCID-X1 gene therapy clinical trials carried out in France and the UK in the 2000s with non-self-inactivating gammaretroviral vectors led to the development of T-cell leukemia in some treated patients.
Genethon therefore worked with international experts in the disease to develop a secure lentiviral vector enabling the expression of an optimized form of this IL2RG gene in patients’ stem cells and immune systems. Genethon has made its preclinical and manufacturing data available to its partners for the preparation of clinical trials.
A clinical trial is currently underway in the UK and the USA. The trial is being conducted by Boston Children’s Hospital and aims to treat 12 patients with two conditioning approaches.
Publications
- Poletti, V., et al. (2018). Preclinical Development of a Lentiviral Vector for Gene Therapy of X-Linked Severe Combined Immunodeficiency, Mol Ther Methods Clin Dev, 9: 257-269.
Severe radio-sensitive combined immunodeficiency (RS-SCID) linked to Artemis protein deficiency: development of a lentiviral gene therapy at Genethon
RS-SCID is a very rare form of SCID, inherited in the autosomal recessive mode. RS-SCID affects both boys and girls. Babies with this type of SCID lack T and B lymphocytes but have NK lymphocytes. The genetic defect is linked to the DCLRE1C gene, which codes for the Artemis protein. This protein plays an essential role in certain key stages of DNA breakage repair. As a result, Artemis is critical to the development of the immune system and the establishment of adaptive immunity. Artemis is essential for the genome rearrangements that create the diversity of the T receptor and immunoglobulin repertoire.
RS-SCID gene therapy is a potential therapeutic alternative for patients without compatible allogeneic stem cell donors, but the gene therapy approach remains unproven in this disease.
Genethon has been working for many years with disease experts to develop a gene therapy for RS-SCID using a safe lentiviral vector expressing physiological levels of the Artemis protein. The positive results of preclinical studies and the production of clinical batches of vectors by Genethon and Yposkesi have made it possible to apply for authorization for a clinical trial of RS-SCID gene therapy led by AP-HP, which has begun at the Necker Hospital in Paris (Coordinating Investigator: Marina Cavazzana). The trial plans to include 5 children.
RS-SCID : le rôle de Généthon et aujourd’hui ?
Généthon collabore depuis de nombreuses années avec les experts de la maladie pour développer une thérapie génique de RS-SCID utilisant un vecteur lentiviral sécurisé et exprimant des niveaux physiologiques de la protéine Artémis.
Les résultats positifs des études précliniques et la production de lot clinique de vecteur par Généthon et Yposkesi ont permis de faire la demande d’autorisation pour un essai clinique de thérapie génique de RS-SCID mené par l’AP-HP qui a démarré à l’hôpital Necker à Paris (Investigateur coordonnateur : Marina Cavazzana). L’essai prévoit d’inclure 5 enfants.
Publications
- Charrier et al. Biosafety Studies of a Clinically Applicable Lentiviral Vector for the Gene Therapy of Artemis-SCID.
- Charrier S, Lagresle-Peyrou C, Poletti V, Rothe M, Cédrone G, Gjata B, Mavilio F, Fischer A, Schambach A, de Villartay JP, Cavazzana M, Hacein-Bey-Abina S, Galy A.Mol Ther Methods Clin Dev. 2019 Sep 13;15:232-245. doi: 10.1016/j.omtm.2019.08.014. eCollection 2019 Dec 13.PMID: 31720302
- Lymphopoiesis in transgenic mice over-expressing Artemis. Rivera-Munoz P, Abramowski V, Jacquot S, André P, Charrier S, Lipson-Ruffert K, Fischer A, Galy A, Cavazzana M, de Villartay JP.Gene Ther. 2016 Feb;23(2):176-86. doi: 10.1038/gt.2015.95. Epub 2015 Oct 1.PMID: 26361272
- Stable and functional lymphoid reconstitution in artemis-deficient mice following lentiviral artemis gene transfer into hematopoietic stem cells. Benjelloun F, Garrigue A, Demerens-de Chappedelaine C, Soulas-Sprauel P, Malassis-Séris M, Stockholm D, Hauer J, Blondeau J, Rivière J, Lim A, Le Lorc’h M, Romana S, Brousse N, Pâques F, Galy A, Charneau P, Fischer A, de Villartay JP, Cavazzana-Calvo M. Mol Ther. 2008 Aug;16(8):1490-9. doi: 10.1038/mt.2008.118. Epub 2008 Jun 17.PMID: 18560421 Free article.
