The Research Project
Pompe disease (PD) is an autosomal recessive disease due to the lack of acid alpha-glucosidase (GAA) enzyme, which is involved in the degradation of lysosomal glycogen. The absence of this enzyme leads to the accumulation of glycogen in the lysosome and to the impairment of the lysosomal functions and autophagy flux. Disease manifestation is prominently muscular, with severe cardiac hypertrophic cardiomyopathy, respiratory function impairment and proximal muscle weakness.
As of 2022, three distinct clinical trials are ongoing to evaluate the efficacy of Adeno-Associated Virus (AAV)-based gene therapy in Pompe disease, one of them developed by Spark Therapeutics in collaboration with Genethon (NCT04093349). Despite encouraging results, treatment-induced immune responses and anti-GAA pre-existing immunity could limit efficacy and application of such AAV-based treatments. The aim of this project is to evaluate in mice models the importance of anti-GAA immune response for efficacy and safety of AAV-mediated GAA delivery and propose new combination of immunosuppressive drugs and AAV vectors for the treatment of populations not previously exposed to the enzyme as well as in GAA-seropositive individuals.
The present project will be developed under the supervision of Dr. David Gross in the “Immunology and liver diseases” team led by Giuseppe Ronzitti, within the UMR_S951 INTEGRARE unit. INTEGRARE is an INSERM unit that regroups more than 80 staff members integrated in the Genethon R&D structure, affiliated with the local University of Evry/University Paris Saclay. Genethon, a non-profit biotherapy organization created by the Association Française contre les Myopathies, is devoted to AAV gene therapy for rare diseases, mainly for neuromuscular diseases, and ensures translational development from research up to clinical validation (https://www.genethon.com/our-pipeline/pompe-disease/).
The applicant: Candidates should have a PhD and a strong background in immunology, with expertise in animal models, cytometry and molecular biology. Motivated candidates with creative and innovative skills, as well as capacity to work within a team, are especially encouraged to apply.
Starting Date: 1st quarter of 2023.
Salary: INSERM, for 2 years, according to experience.
Applications: in English including a cover letter, a detailed CV with publication list and references should be sent to David Gross at [email protected]
Recent publications of the team
Gross DA, Tedesco N, Leborgne C, Ronzitti G. Overcoming the Challenges Imposed by Humoral Immunity to AAV Vectors to Achieve Safe and Efficient Gene Transfer in Seropositive Patients. Front Immunol. 2022 Apr 7;13:857276.
Rossignol J, Belaid Z, Fouquet G, Guillem F, Rignault R, Milpied P, Renand A, Coman T, D’Aveni M, Dussiot M, Colin E, Levy J, Carvalho C, Goudin N, Cagnard N, Côté F, Babdor J, Bhukhai K, Polivka L, Bigorgne AE, Halse H, Marabelle A, Mouraud S, Lepelletier Y, Maciel TT, Rubio MT, Heron D, Robert C, Girault I, Lebeherec D, Scoazec JY, Moura I, Condon L, Weimershaus M, Pages F, Davoust J, Gross D, Hermine O. Neuropilin-1 cooperates with PD-1 in CD8+ T cells predicting outcomes in melanoma patients treated with anti-PD1. iScience. 2022 May 5;25(6):104353.
Zhukouskaya VV, Jauze L, Charles S, Leborgne C, Hilliquin S, Sadoine J, Slimani L, Baroukh B, van Wittenberghe L, Danièle N, Rajas F, Linglart A, Mingozzi F, Chaussain C, Bardet C, Ronzitti G. A novel therapeutic strategy for skeletal disorders: Proof of concept of gene therapy for X-linked hypophosphatemia. Sci Adv. 2021 Oct 29;7(44)
Costa-Verdera H, Collaud F, Riling CR, Sellier P, Nordin JML, Preston GM, Cagin U, Fabregue J, Barral S, Moya-Nilges M, Krijnse-Locker J, van Wittenberghe L, Daniele N, Gjata B, Cosette J, Abad C, Simon-Sola M, Charles S, Li M, Crosariol M, Antrilli T, Quinn WJ 3rd, Gross DA, Boyer O, Anguela XM, Armour SM, Colella P, Ronzitti G, Mingozzi F. Hepatic expression of GAA results in enhanced enzyme bioavailability in mice and non-human primates. Nat Commun. 2021 Nov 4;12(1):6393
Cagin U, Puzzo F, Gomez MJ, Moya-Nilges M, Sellier P, Abad C, Van Wittenberghe L, Daniele N, Guerchet N, Gjata B, Collaud F, Charles S, Sola MS, Boyer O, Krijnse-Locker J, Ronzitti G, Colella P, Mingozzi F. Rescue of Advanced Pompe Disease in Mice with Hepatic Expression of Secretable Acid α-Glucosidase. Mol Ther. 2020 Sep 2;28(9):2056-2072.
Ronzitti G, Gross DA, Mingozzi F. Human Immune Responses to Adeno-Associated Virus (AAV) Vectors. Front Immunol. 2020 Apr 17;11:670.
Leborgne C, Barbon E, Alexander JM, Hanby H, Delignat S, Cohen DM, Collaud F, Muraleetharan S, Lupo D, Silverberg J, Huang K, van Wittengerghe L, Marolleau B, Miranda A, Fabiano A, Daventure V, Beck H, Anguela XM, Ronzitti G, Armour SM, Lacroix-Desmazes S, Mingozzi F. IgG-cleaving endopeptidase enables in vivo gene therapy in the presence of anti-AAV neutralizing antibodies. Nat Med. 2020 Jul;26(7):1096-1101
Evnouchidou I, Chappert P, Benadda S, Zucchetti A, Weimershaus M, Bens M, Caillens V, Koumantou D, Lotersztajn S, van Endert P, Davoust J, Guermonprez P, Hivroz C, Gross DA, Saveanu L. IRAP-dependent endosomal T cell receptor signalling is essential for T cell responses. Nat Commun. 2020 Jun 2;11(1):2779.
Bartolo L, Li Chung Tong S, Chappert P, Urbain D, Collaud F, Colella P, Richard I, Ronzitti G, Demengeot J, Gross DA, Mingozzi F and Davoust J. Dual muscle-liver transduction imposes immune tolerance for muscle transgene engraftment despite pre-existing immunity. J. Clin. Invest. Ins. 2019 Jun 6;4(11).
Poupiot J, Costa Verdera H, Hardet R, Colella P, Collaud F, Bartolo L, Davoust J, Sanatine P, Mingozzi F, Richard I, Ronzitti G. Role of Regulatory T Cell and Effector T Cell Exhaustion in Liver-Mediated Transgene Tolerance in Muscle. Mol Ther Methods Clin Dev. 2019 Sep 3;15:83-100.
Lalfer M, Chappert P, Carpentier M, Urbain D, Davoust J and Gross DA. Foxp3+ regulatory and conventional CD4+ T cells display similarly high frequencies of alloantigen-reactive cells. Front. Immunol. 2019 Mar 19;10:521.
Gross DA, Ghenassia A, Bartolo L, Urbain D, Benkhelifa-Ziyyat S, Lorain S, Davoust J and Chappert P. Cross-presentation of skin-targeted rAAV2/1 transgene induces potent resident memory CD8+ T cell responses. J. Virol. 2019 Feb 19;93(5).