Overcoming Preexisting Humoral Immunity to AAV Using Capsid Decoys
| Autor: | Alex Tai, Federico Mingozzi, J F Wright, Carolann Howard, Daniel J. Hui, Giulia Pavani, Christian Hinderer, Yifeng Chen, Xavier M. Anguela, Gregory M. Podsakoff, Liron Elkouby, Armida Faella, Robert J. Davidson, Shangzhen Zhou, Etiena Basner-Tschakarjan, Katherine A. High, Mustafa N. Yazicioglu |
|---|---|
| Přispěvatelé: | Immunologie moléculaire et biothérapies innovantes (IMBI), Généthon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Évry-Val-d'Essonne (UEVE)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Technologies et systèmes d'information pour les agrosystèmes (UR TSCF), Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA), Department of Applied Mathematics [Hong Kong], The Hong Kong Polytechnic University [Hong Kong] (POLYU), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon |
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Male
viruses [SDV]Life Sciences [q-bio] Mutant Cell Antibodies Viral Article Virus Mice 03 medical and health sciences Transduction (genetics) Capsid 0302 clinical medicine Neutralization Tests Immunity medicine Animals Humans 030304 developmental biology 0303 health sciences biology Gene Transfer Techniques General Medicine Dependovirus Antibodies Neutralizing Macaca mulatta Virology Immunity Humoral 3. Good health Mice Inbred C57BL medicine.anatomical_structure 030220 oncology & carcinogenesis Mutation Humoral immunity biology.protein Antibody |
| Zdroj: | Sci Transl Med Sci Transl Med, 2013, 5 (194), pp.194ra92. ⟨10.1126/scitranslmed.3005795⟩ |
| DOI: | 10.1126/scitranslmed.3005795⟩ |
| Popis: | International audience; Adeno-associated virus (AAV) vectors delivered through the systemic circulation successfully transduce various target tissues in animal models. However, similar attempts in humans have been hampered by the high prevalence of neutralizing antibodies to AAV, which completely block vector transduction. We show in both mouse and nonhuman primate models that addition of empty capsid to the final vector formulation can, in a dose-dependent manner, adsorb these antibodies, even at high titers, thus overcoming their inhibitory effect. To further enhance the safety of the approach, we mutated the receptor binding site of AAV2 to generate an empty capsid mutant that can adsorb antibodies but cannot enter a target cell. Our work suggests that optimizing the ratio of full/empty capsids in the final formulation of vector, based on a patient's anti-AAV titers, will maximize the efficacy of gene transfer after systemic vector delivery. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|