title: Impact of AAV Capsid-Specific T-Cell Responses on Design and Outcome of Clinical Gene Transfer Trials with Recombinant Adeno-Associated Viral Vectors: An Evolving Controversy.
abstract: Recombinant adenovirus-associated (rAAV) vectors due to their ease of construction, wide tissue tropism, and lack of pathogenicity remain at the forefront for long-term gene replacement therapy. In spite of very encouraging preclinical results, clinical trials were initially unsuccessful; expression of the rAAV vector-delivered therapeutic protein was transient. Loss of expression was linked to an expansion of AAV capsid-specific T-cell responses, leading to the hypothesis that rAAV vectors recall pre-existing memory T cells that had been induced by natural infections with AAV together with a helper virus. Although this was hotly debated at first, AAV capsid-specific T-cell responses were observed in several gene transfer trials that used high doses of rAAV vectors. Subsequent trials designed to circumvent these T-cell responses through the use of immunosuppressive drugs, rAAV vectors based on rare serotypes, or modified to allow for therapeutic levels of the transgene product at low, non-immunogenic vector doses are now successful in correcting debilitating diseases.
authors.affiliation: 1 Wistar Institute , Philadelphia, Pennsylvania.
authors.forename: Hildegund C J
authors.initials: HCJ
authors.lastname: Ertl
authors.affiliation: 2 Spark Therapeutics , Philadelphia, Pennsylvania.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: High
mesh_terms: D036022:Capsid Proteins / Q000276:immunology / Q000627:therapeutic use*; D000229:Dependovirus / Q000235:genetics* / Q000276:immunology; D018014:Gene Transfer Techniques / Q000009:adverse effects; D015316:Genetic Therapy / Q000009:adverse effects; D005822:Genetic Vectors / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D006801:Humans; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D036022:Capsid Proteins
keywords: adeno-associated virus vector; dose response; gene transfer; immune response; immuno-suppression