Blood and Immune Diseases

UCBCD34_markCD34LDLR_AV2015Inherited genetic diseases that affect the blood or the immune system can become debilitating and reduce life expectancy when causing recurrent infections, cancers, hemorrhages, anemias or organ damage. Severe immune deficiencies of genetic origin have been the first types of diseases for which gene therapy was tried in humans. These pioneering studies showed that it was possible to achieve long-term gene marking in blood cells and that gene therapy could potentially provide significant health benefits. However, the design of safe gene therapy vectors, their effective delivery to patients cells and the establishment of complete biological and therapeutic efficacy remain important challenges in each specific disease tested. Furthermore, the production of gene therapy vectors for clinical use remains complex and costly, therefore must be improved to develop this new class of biotherapies. Advances in gene therapy for rare pathologies may not only respond to unmet medical needs but may promote innovation in more frequent diseases such as leukemias or infectious diseases on the basis of similar technologies.  Currently no gene therapy is yet registered for any of the inherited or acquired blood or immune diseases.

The Blood and Immune Diseases Program at Genethon is developing gene therapies for a series of molecularly well-characterized rare diseases. Currently, the approach is based on ex vivo lentiviral vector-mediated gene transfer into patient autologous hematopoietic stem cells. Phase I/II clinical trials are conducted with international networks of centers and collaborators. Trials are ongoing to treat Wiskott Aldrich Syndrome (WAS), a primary immune deficiency complicated by platelet defects; X-linked chronic granulomatous disease (X-CGD) a primary immune deficiency due to phagocyte defects, Fanconi Anemia type A (FA) a DNA repair defect leading to pancytopenia. Trials are in preparation for several forms of severe combined immunodeficiency (SCID); Artemis-SCID and X-linked SCID (SCID-X1) causing profound immune defects. Gene therapy is also in preparation for sickle cell disease. An important underlying benefit of this program is to promote technology improvements through the various needs of projects. Gene editing is explored as a new technology to achieve more specific gene correction than gene transfer. Industrial scale automated production of lentiviral vectors is also ongoing to respond to increasing clinical needs.

Genethon has recently obtained encouraging results in Wiskott Aldrich Syndrome. We are developing a new gene therapy for this disease through phase I/II trials that are ongoing in Europe and in the US. Results from the first patients treated in Europe show that the approach is well tolerated, safe and efficacious. Patients improved their immune function, resolved their eczema, had fewer bleeding episodes and no adverse event was caused by the vector in patients followed between 9 and 42 months after gene therapy (Hacein-Bey Abina and Gaspar et al. JAMA 2015).  Future perspectives are to bring this new therapy to patients.



Lentiviral vectors, hematopoietic gene therapy, immune system, hematopiesis, primary immune deficiency.


SELECTED PUBLICATIONS (Link to Genethon’s publications)

  1. Hacein-Bey Abina, H. B. Gaspar, J. Blondeau, L. Caccavelli, S. Charrier, K. Buckland, C. Picard, E. Six, N. Himoudi, K. Gilmour, A. M. McNicol, H. Hara, J. Xu-Bayford, C. Rivat, F. Touzot, F. Mavilio, A. Lim, J. M. Treluyer, S. Heritier, F. Lefrere, J. Magalon, I. Pengue-Koyi, G. Honnet, S. Blanche, E. A. Sherman, F. Male, C. Berry, N. Malani, F. D. Bushman, A. Fischer, A. J. Thrasher, A. Galy, and M. Cavazzana, ‘Outcomes Following Gene Therapy in Patients with Severe Wiskott-Aldrich Syndrome’, JAMA, 313 (2015), 1550-63.
  2. Marini, A. Kertesz-Farkas, H. Ali,  B. Lucic, K. Lisek, L.Manganaro,S. Pongor, R. Luzzati, A. Recchia, F. Mavilio, M. Giacca, M. Lusic ‘Nuclear architecture dictates HIV-1 integration site selection’  Nature 521, 227–231 (14 May 2015)
  3. Aiuti, L. Biasco, S. Scaramuzza, F. Ferrua, M. P. Cicalese, C. Baricordi, F. Dionisio, A. Calabria, S. Giannelli, M. C. Castiello, M. Bosticardo, C. Evangelio, A. Assanelli, M. Casiraghi, S. Di Nunzio, L. Callegaro, C. Benati, P. Rizzardi, D. Pellin, C. Di Serio, M. Schmidt, C. Von Kalle, J. Gardner, N. Mehta, V. Neduva, D. J. Dow, A. Galy, R. Miniero, A. Finocchi, A. Metin, P. P. Banerjee, J. S. Orange, S. Galimberti, M. G. Valsecchi, A. Biffi, E. Montini, A. Villa, F. Ciceri, M. G. Roncarolo, and L. Naldini, ‘Lentiviral Hematopoietic Stem Cell Gene Therapy in Patients with Wiskott-Aldrich Syndrome’, Science, 341 (2013), 1233151.
  4. B. Kaufmann, H. Buning, A. Galy, A. Schambach, and M. Grez, ‘Gene Therapy on the Move’, EMBO Mol Med, 5 (2013), 1642-61. Review.
  5. O. W. Merten, S. Charrier, N. Laroudie, S. Fauchille, C. Dugue, C. Jenny, M. Audit, M. A. Zanta-Boussif, H. Chautard, M. Radrizzani, G. Vallanti, L. Naldini, P. Noguiez-Hellin, and A. Galy, ‘Large Scale Manufacture and Characterisation of a Lentiviral Vector Produced for Clinical Ex Vivo Gene Therapy Application’, Hum Gene Ther (2010).


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