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Immunology of gene transfer: a crucial issue

The immune system, a vital ally to be understood to make gene therapy treatments even more accessible. Around fifteen experts at Genethon are committed to identifying and controlling interactions between the immune system and gene therapy vectors.

The function of the immune system is to preserve the body’s integrity by neutralizing elements that too heavily disrupt the balance that it maintains with its environment. It learns not to react to the food that we ingest, or the pollen that we breathe in, while retaining its ability to counteract a pathogen that has become too invasive. Drug genes are brought into the cells by carriers, “vectors” of viral origin. This can lead the immune system to get confused and want to reject the treatment, limiting its therapeutic effectiveness and causing adverse effects.

Work conducted for the last twenty years has helped refine immuno-modulating treatments, able to better control these adverse effects against gene therapy treatment while preserving the immune system’s essential protective function.   Furthermore, a number of parameters have been identified that influence the occurrence of immune responses, such as constitution of the drug vector itself or its ability to screen a particular tissue in the body. In some clinical trials, long-term therapeutic benefits were obtained over the course of around fifteen years. 

Limits remain, however, such as the ineligibility of patients with natural immunity against the vector or who develop a response directed against the gene drug, or the possibility of treating a young patient several times if they need it.

An Immunology program at Genethon

Aware of the essential issue of immune responses for the introduction of gene therapy treatments that are safe and accessible to as many patients as possible, Genethon pursues an Immunology program, which three areas of focus are:

-identification of new immuno-modulating pathways to overcome the current limits imposed by the immune system,
-better characterization of interactions between the immune system and gene transfer vectors,
-preclinical and clinical follow-up (biomarkers, immuno-monitoring) of immune responses.

Within Genethon and/or members of UMR Inserm S951 – Integrare (Immunology and Liver Diseases team and Immunology and Biotherapies team), around 15 people work on this program devoted to immunology, including researchers, post-doctoral fellows, technicians and engineers, as well as PhD students.

The program uses Genethon’s platforms/services:  3 cytometers (Cytoflex LX, Cytoflex S , Sony SP6800) and a MoFlo Astrios EQ cell sorter; several imaging machines (confocal TCS SP8 Leica, AMNIS Image Stream); immunohistochemistry; production of AAV and lentiviral vectors; and an animal facility managed by the Genopole at Evry, where Genethon has several dozen strains.

They support us

Recent publications

  1. Durable immunogenicity, adaptation to emerging variants, and low-dose efficacy of an AAV-based COVID-19 vaccine platform in macaques. N. Zabaleta, U. Bhatt, C. Hérate, P. Maisonnasse, J. Sanmiguel, C. Diop, S. Castore, R. Estelien, D. Li, N. Dereuddre-Bosquet, M. Cavarelli, A.S. Gallouët, Q. Pascal, T. Naninck, N. Kahlaoui, J. Lemaitre, F. Relouzat, G. Ronzitti, H.J. Thibaut, E. Montomoli, J.M. Wilson, R. Le Grand, and L.H. Vandenberghe. Mol Ther 2022. 30, 2952-2967.
  2. Neuropilin-1 cooperates with PD-1 in CD8(+) T cells predicting outcomes in melanoma patients treated with anti-PD1. J. Rossignol, Z. Belaid, G. Fouquet, F. Guillem, R. Rignault, P. Milpied, A. Renand, T. Coman, M. D’Aveni, M. Dussiot, E. Colin, J. Levy, C. Carvalho, N. Goudin, N. Cagnard, F. Côté, J. Babdor, K. Bhukhai, L. Polivka, A.E. Bigorgne, H. Halse, A. Marabelle, S. Mouraud, Y. Lepelletier, T.T. Maciel, M.T. Rubio, D. Heron, C. Robert, I. Girault, D. Lebeherec, J.Y. Scoazec, I. Moura, L. Condon, M. Weimershaus, F. Pages, J. Davoust, D. Gross, and O. Hermine. iScience 2022. 25, 104353.
  3. Long-term safety and efficacy of lentiviral hematopoietic stem/progenitor cell gene therapy for Wiskott-Aldrich syndrome. A. Magnani, M. Semeraro, F. Adam, C. Booth, L. Dupré, E.C. Morris, A. Gabrion, C. Roudaut, D. Borgel, A. Toubert, E. Clave, C. Abdo, G. Gorochov, R. Petermann, M. Guiot, M. Miyara, D. Moshous, E. Magrin, A. Denis, F. Suarez, C. Lagresle, A.M. Roche, J. Everett, A. Trinquand, M. Guisset, J.X. Bayford, S. Hacein-Bey-Abina, A. Kauskot, R. Elfeky, C. Rivat, S. Abbas, H.B. Gaspar, E. Macintyre, C. Picard, F.D. Bushman, A. Galy, A. Fischer, E. Six, A.J. Thrasher, and M. Cavazzana. Nat Med 2022. 28, 71-80.
  4. Overcoming the Challenges Imposed by Humoral Immunity to AAV Vectors to Achieve Safe and Efficient Gene Transfer in Seropositive Patients. D.A. Gross, N. Tedesco, C. Leborgne, and G. Ronzitti. Front Immunol 2022. 13, 857276.
  5. Cytokines, chemokines and growth factors profile in human aqueous humor in idiopathic uveitis. M.H. Errera, A. Pratas, S. Fisson, T. Manicom, M. Boubaya, N. Sedira, E. Héron, L. Merabet, A. Kobal, V. Levy, J.M. Warnet, C. Chaumeil, F. Brignole-Baudouin, J.A. Sahel, P. Goldschmidt, B. Bodaghi, and C. Bloch-Queyrat. PLoS One 2022. 17, e0254972.
  6. Lentiviral standards to determine the sensitivity of assays that quantify lentiviral vector copy numbers and genomic insertion sites in cells. G. Corre, A. Seye, S. Frin, M. Ferrand, K. Winkler, C. Luc, F. Dorange, C.J. Rocca, and A. Galy. Gene Ther 2022.
  7. Systemic and local immune responses to intraocular AAV vector administration in non-human primates. D. Ail, D. Ren, E. Brazhnikova, C. Nouvel-Jaillard, S. Bertin, S.B. Mirashrafi, S. Fisson, and D. Dalkara. Molecular therapy. Methods & clinical development 2022. 24, 306-316.
  8. Early Phase Clinical Immunogenicity of Valoctocogene Roxaparvovec, an AAV5-Mediated Gene Therapy for Hemophilia A. B.R. Long, P. Veron, K. Kuranda, R. Hardet, N. Mitchell, G.M. Hayes, W.Y. Wong, K. Lau, M. Li, M.B. Hock, S.J. Zoog, C. Vettermann, F. Mingozzi, and B. Schweighardt. Mol Ther 2021. 29, 597-610.
  9. A combination of cyclophosphamide and interleukin-2 allows CD4+ T cells converted to Tregs to control scurfy syndrome. M. Delville, F. Bellier, J. Leon, R. Klifa, S. Lizot, H. Vinçon, S. Sobrino, R. Thouenon, A. Marchal, A. Garrigue, J. Olivré, S. Charbonnier, C. Lagresle-Peyrou, M. Amendola, A. Schambach, D. Gross, B. Lamarthée, C. Benoist, J. Zuber, I. André, M. Cavazzana, and E. Six. Blood 2021. 137, 2326-2336.
  10. Clonal tracking in gene therapy patients reveals a diversity of human hematopoietic differentiation programs. E. Six, A. Guilloux, A. Denis, A. Lecoules, A. Magnani, R. Vilette, F. Male, N. Cagnard, M. Delville, E. Magrin, L. Caccavelli, C. Roudaut, C. Plantier, S. Sobrino, J. Gregg, C.L. Nobles, J.K. Everett, S. Hacein-Bey-Abina, A. Galy, A. Fischer, A.J. Thrasher, I. André, M. Cavazzana, and F.D. Bushman. Blood 2020. 135, 1219-1231.
  11. Human Immune Responses to Adeno-Associated Virus (AAV) Vectors. G. Ronzitti, D.A. Gross, and F. Mingozzi. Front Immunol 2020. 11, 670.
  12. IgG-cleaving endopeptidase enables in vivo gene therapy in the presence of anti-AAV neutralizing antibodies. C. Leborgne, E. Barbon, J.M. Alexander, H. Hanby, S. Delignat, D.M. Cohen, F. Collaud, S. Muraleetharan, D. Lupo, J. Silverberg, K. Huang, L. van Wittengerghe, B. Marolleau, A. Miranda, A. Fabiano, V. Daventure, H. Beck, X.M. Anguela, G. Ronzitti, S.M. Armour, S. Lacroix-Desmazes, and F. Mingozzi. Nat Med 2020. 26, 1096-1101.
  13. Lentiviral gene therapy for X-linked chronic granulomatous disease. D.B. Kohn, C. Booth, E.M. Kang, S.Y. Pai, K.L. Shaw, G. Santilli, M. Armant, K.F. Buckland, U. Choi, S.S. De Ravin, M.J. Dorsey, C.Y. Kuo, D. Leon-Rico, C. Rivat, N. Izotova, K. Gilmour, K. Snell, J.X. Dip, J. Darwish, E.C. Morris, D. Terrazas, L.D. Wang, C.A. Bauser, T. Paprotka, D.B. Kuhns, J. Gregg, H.E. Raymond, J.K. Everett, G. Honnet, L. Biasco, P.E. Newburger, F.D. Bushman, M. Grez, H.B. Gaspar, D.A. Williams, H.L. Malech, A. Galy, and A.J. Thrasher. Nat Med 2020. 26, 200-206.
  14. IRAP-dependent endosomal T cell receptor signalling is essential for T cell responses. I. Evnouchidou, P. Chappert, S. Benadda, A. Zucchetti, M. Weimershaus, M. Bens, V. Caillens, D. Koumantou, S. Lotersztajn, P. van Endert, J. Davoust, P. Guermonprez, C. Hivroz, D.A. Gross, and L. Saveanu. Nat Commun 2020. 11, 2779.
  15. Of rAAV and Men: From Genetic Neuromuscular Disorder Efficacy and Toxicity Preclinical Studies to Clinical Trials and Back. L. Buscara, D.A. Gross, and N. Daniele. Journal of personalized medicine 2020. 10.
  16. Capsid-specific removal of circulating antibodies to adeno-associated virus vectors. B. Bertin, P. Veron, C. Leborgne, J.Y. Deschamps, S. Moullec, Y. Fromes, F. Collaud, S. Boutin, V. Latournerie, L. van Wittenberghe, B. Delache, R. Le Grand, N. Dereuddre-Bosquet, O. Benveniste, P. Moullier, C. Masurier, O. Merten, and F. Mingozzi. Scientific reports 2020. 10, 864.
  17. Vectofusin-1 Improves Transduction of Primary Human Cells with Diverse Retroviral and Lentiviral Pseudotypes, Enabling Robust, Automated Closed-System Manufacturing. C. Radek, O. Bernadin, K. Drechsel, N. Cordes, R. Pfeifer, P. Sträßer, M. Mormin, A. Gutierrez-Guerrero, F.L. Cosset, A.D. Kaiser, T. Schaser, A. Galy, E. Verhoeyen, and I.C.D. Johnston. Hum Gene Ther 2019. 30, 1477-1493.
  18. Role of Regulatory T Cell and Effector T Cell Exhaustion in Liver-Mediated Transgene Tolerance in Muscle. J. Poupiot, H. Costa Verdera, R. Hardet, P. Colella, F. Collaud, L. Bartolo, J. Davoust, P. Sanatine, F. Mingozzi, I. Richard, and G. Ronzitti. Molecular therapy. Methods & clinical development 2019. 15, 83-100.
  19. Prevalence and long-term monitoring of humoral immunity against adeno-associated virus in Duchenne Muscular Dystrophy patients. C. Leborgne, V. Latournerie, S. Boutin, D. Desgue, A. Quéré, E. Pignot, F. Collaud, S. Charles, M. Simon Sola, E. Masat, F. Jouen, O. Boyer, C. Masurier, F. Mingozzi, and P. Veron. Cell Immunol 2019. 342, 103780.
  20. Foxp3(+) Regulatory and Conventional CD4(+) T Cells Display Similarly High Frequencies of Alloantigen-Reactive Cells. M. Lalfer, P. Chappert, M. Carpentier, D. Urbain, J.M. Davoust, and D.A. Gross. Front Immunol 2019. 10, 521.
  21. Induction of tumor-specific CTL responses using the C-terminal fragment of Viral protein R as cell penetrating peptide. D.A. Gross, C. Leborgne, P. Chappert, C. Masurier, M. Leboeuf, V. Monteilhet, S. Boutin, F.A. Lemonnier, J. Davoust, and A. Kichler. Scientific reports 2019. 9, 3937.
  22. Cross-Presentation of Skin-Targeted Recombinant Adeno-associated Virus 2/1 Transgene Induces Potent Resident Memory CD8(+) T Cell Responses. D.A. Gross, A. Ghenassia, L. Bartolo, D. Urbain, S. Benkhelifa-Ziyyat, S. Lorain, J. Davoust, and P. Chappert. J Virol 2019. 93.
  23. Temporary Reduction of Membrane CD4 with the Antioxidant MnTBAP Is Sufficient to Prevent Immune Responses Induced by Gene Transfer. S. Da Rocha, J. Bigot, F. Onodi, J. Cosette, G. Corre, J. Poupiot, D. Fenard, B. Gjata, A. Galy, and T.M.A. Neildez-Nguyen. Molecular therapy. Methods & clinical development 2019. 14, 285-299.
  24. Dual muscle-liver transduction imposes immune tolerance for muscle transgene engraftment despite preexisting immunity. L. Bartolo, S. Li Chung Tong, P. Chappert, D. Urbain, F. Collaud, P. Colella, I. Richard, G. Ronzitti, J. Demengeot, D.A. Gross, F. Mingozzi, and J. Davoust. JCI insight 2019. 4.
  25. Prevalence and Relevance of Pre-Existing Anti-Adeno-Associated Virus Immunity in the Context of Gene Therapy for Crigler-Najjar Syndrome. S.J. Aronson, P. Veron, F. Collaud, A. Hubert, V. Delahais, G. Honnet, R.J. de Knegt, N. Junge, U. Baumann, A. Di Giorgio, L. D’Antiga, V.M. Ginocchio, N. Brunetti-Pierri, P. Labrune, U. Beuers, P.J. Bosma, and F. Mingozzi. Hum Gene Ther 2019. 30, 1297-1305.
  26. Subretinal Injection of HY Peptides Induces Systemic Antigen-Specific Inhibition of Effector CD4(+) and CD8(+) T-Cell Responses. J. Vendomèle, S. Dehmani, Q. Khebizi, A. Galy, and S. Fisson. Front Immunol 2018. 9, 504.
  27. Combination Therapy Is the New Gene Therapy? G. Ronzitti, and F. Mingozzi. Mol Ther 2018. 26, 12-14.
  28. Antigen-selective modulation of AAV immunogenicity with tolerogenic rapamycin nanoparticles enables successful vector re-administration. A. Meliani, F. Boisgerault, R. Hardet, S. Marmier, F. Collaud, G. Ronzitti, C. Leborgne, H. Costa Verdera, M. Simon Sola, S. Charles, A. Vignaud, L. van Wittenberghe, G. Manni, O. Christophe, F. Fallarino, C. Roy, A. Michaud, P. Ilyinskii, T.K. Kishimoto, and F. Mingozzi. Nat Commun 2018. 9, 4098.
  29. Prevalence and long-term monitoring of humoral immunity against adeno-associated virus in Duchenne Muscular Dystrophy patients. C. Leborgne, V. Latournerie, S. Boutin, D. Desgue, A. Quere, E. Pignot, F. Collaud, S. Charles, M. Simon Sola, E. Masat, F. Jouen, O. Boyer, C. Masurier, F. Mingozzi, and P. Veron. Cell Immunol 2018.
  30. Exposure to wild-type AAV drives distinct capsid immunity profiles in humans. K. Kuranda, P. Jean-Alphonse, C. Leborgne, R. Hardet, F. Collaud, S. Marmier, H. Costa Verdera, G. Ronzitti, P. Veron, and F. Mingozzi. J Clin Invest 2018. 128, 5267-5279.
  31. Dosage Thresholds and Influence of Transgene Cassette in Adeno-Associated Virus-Related Toxicity. H. Khabou, C. Cordeau, L. Pacot, S. Fisson, and D. Dalkara. Hum Gene Ther 2018. 29, 1235-1241.
  32. Influence of Pre-existing Anti-capsid Neutralizing and Binding Antibodies on AAV Vector Transduction. Z. Fitzpatrick, C. Leborgne, E. Barbon, E. Masat, G. Ronzitti, L. van Wittenberghe, A. Vignaud, F. Collaud, S. Charles, M. Simon Sola, F. Jouen, O. Boyer, and F. Mingozzi. Molecular therapy. Methods & clinical development 2018. 9, 119-129.
  33. Emerging Issues in AAV-Mediated In Vivo Gene Therapy. P. Colella, G. Ronzitti, and F. Mingozzi. Molecular therapy. Methods & clinical development 2018. 8, 87-104.
  34. Induction of anergic or regulatory tumor-specific CD4(+) T cells in the tumor-draining lymph node. R. Alonso, H. Flament, S. Lemoine, C. Sedlik, E. Bottasso, I. Peguillet, V. Premel, J. Denizeau, M. Salou, A. Darbois, N.G. Nunez, B. Salomon, D. Gross, E. Piaggio, and O. Lantz. Nat Commun 2018. 9, 2113.
  35. Vectofusin-1, a potent peptidic enhancer of viral gene transfer forms pH-dependent α-helical nanofibrils, concentrating viral particles. L.S. Vermeer, L. Hamon, A. Schirer, M. Schoup, J. Cosette, S. Majdoul, D. Pastré, D. Stockholm, N. Holic, P. Hellwig, A. Galy, D. Fenard, and B. Bechinger. Acta biomaterialia 2017. 64, 259-268.
  36. Cellular and Molecular Mechanisms of Anterior Chamber-Associated Immune Deviation (ACAID): What We Have Learned from Knockout Mice. J. Vendomèle, Q. Khebizi, and S. Fisson. Front Immunol 2017. 8, 1686.
  37. Enhanced liver gene transfer and evasion of preexisting humoral immunity with exosome-enveloped AAV vectors. A. Meliani, F. Boisgerault, Z. Fitzpatrick, S. Marmier, C. Leborgne, F. Collaud, M. Simon Sola, S. Charles, G. Ronzitti, A. Vignaud, L. van Wittenberghe, B. Marolleau, F. Jouen, S. Tan, O. Boyer, O. Christophe, A.R. Brisson, C.A. Maguire, and F. Mingozzi. Blood advances 2017. 1, 2019-2031.
  38. Peptides derived from evolutionarily conserved domains in Beclin-1 and Beclin-2 enhance the entry of lentiviral vectors into human cells. S. Majdoul, J. Cosette, A.K. Seye, E. Bernard, S. Frin, N. Holic, N. Chazal, L. Briant, L. Espert, A. Galy, and D. Fenard. J Biol Chem 2017. 292, 18672-18681.
  39. Systemic AAV8-Mediated Gene Therapy Drives Whole-Body Correction of Myotubular Myopathy in Dogs. D.L. Mack, K. Poulard, M.A. Goddard, V. Latournerie, J.M. Snyder, R.W. Grange, M.R. Elverman, J. Denard, P. Veron, L. Buscara, C. Le Bec, J.Y. Hogrel, A.G. Brezovec, H. Meng, L. Yang, F. Liu, M. O’Callaghan, N. Gopal, V.E. Kelly, B.K. Smith, J.L. Strande, F. Mavilio, A.H. Beggs, F. Mingozzi, M.W. Lawlor, A. Buj-Bello, and M.K. Childers. Mol Ther 2017. 25, 839-854.
  40. Long-term microdystrophin gene therapy is effective in a canine model of Duchenne muscular dystrophy. C. Le Guiner, L. Servais, M. Montus, T. Larcher, B. Fraysse, S. Moullec, M. Allais, V. François, M. Dutilleul, A. Malerba, T. Koo, J.L. Thibaut, B. Matot, M. Devaux, J. Le Duff, J.Y. Deschamps, I. Barthelemy, S. Blot, I. Testault, K. Wahbi, S. Ederhy, S. Martin, P. Veron, C. Georger, T. Athanasopoulos, C. Masurier, F. Mingozzi, P. Carlier, B. Gjata, J.Y. Hogrel, O. Adjali, F. Mavilio, T. Voit, P. Moullier, and G. Dickson. Nat Commun 2017. 8, 16105.
  41. Low-Dose Liver-Targeted Gene Therapy for Pompe Disease Enhances Therapeutic Efficacy of ERT via Immune Tolerance Induction. S.O. Han, G. Ronzitti, B. Arnson, C. Leborgne, S. Li, F. Mingozzi, and D. Koeberl. Molecular therapy. Methods & clinical development 2017. 4, 126-136.
  42. Intradermal Immunization with rAAV1 Vector Induces Robust Memory CD8(+) T Cell Responses Independently of Transgene Expression in DCs. A. Ghenassia, D.A. Gross, S. Lorain, F. Tros, D. Urbain, S. Benkhelifa-Ziyyat, A. Charbit, J. Davoust, and P. Chappert. Mol Ther 2017. 25, 2309-2322.