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    METHODS FOR PREVENTING INDUCTION OF IMMUNE RESPONSES TO THE TRANSDUCED CELLS EXPRESSING A TRANSGENE PRODUCT AFTER OCULAR GENE THERAPY
    6.
    发明公开
    METHODS FOR PREVENTING INDUCTION OF IMMUNE RESPONSES TO THE TRANSDUCED CELLS EXPRESSING A TRANSGENE PRODUCT AFTER OCULAR GENE THERAPY 审中-公开

    公开(公告)号：US20230190956A1

    公开(公告)日：2023-06-22

    申请号：US17996987

    申请日：2021-04-23

    Applicant: INSERM (Institut National de la Santé et de la Recherche Médicale) ,  Genethon ,  Université d'Evry-Val-d'Essonne

    Inventor： Fisson SYLVAIN

    IPC: A61K48/00 ,  A61K38/16 ,  A61P27/02

    CPC classification number: A61K48/005 ,  A61K48/0083 ,  A61K48/0075 ,  A61K38/162 ,  A61P27/02 ,  C12N2750/14133 ,  C12N2750/14143

    Abstract: Despite the eye's immune-privileged status, a secondary loss of vision in some patients treated with AAV led the inventors to question the immunogenicity of AAV vectors after a subretinal injection. The inventors thus characterized anti-transgene and anti-capsid immune responses induced in the periphery after the subretinal AAV injection. Different doses of AAV8 encoding reporter proteins fused with the HY male antigen were injected at day 0 into the subretinal space of adult immunocompetent C57BL/6 female mice. Subretinal AAV injection induced a dose-dependent proinflammatory immune response to the transgene product, correlated with local transgene expression. In order to trigger a subretinal-associated immune inhibition (SRAII) mechanism, some mice were co-injected subretinally at day 0 with AAV and HY peptides. Interestingly, this subretinal co-injection of AAV8 with peptides of the transgene product modulated the anti-transgene T-cell immune response, even at high dose of vector (5.1010 vg). This immunodulation was also confirmed in a pathophysiological murine model of retinal degeneration. The inventors also demonstrated that injection of AAV8 in the subretinal space induces proinflammatory peripheral immune responses to the transgene and the capsid that could be counteracted y co-injection with transgene peptides. Accordingly, the object of the present invention is to provide methods for preventing induction of immune responses to the transgene product and the AAV capsid after ocular gene therapy.

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