title: Immune responses to AAV in clinical trials.
abstract: Recent findings in a clinical trial in which an adeno-associated virus (AAV) vector expressing coagulation factor IX (F.IX) was introduced into the liver of hemophilia B subjects highlighted a new issue previously not identified in animal studies. Upon AAV gene transfer to liver, two subjects enrolled in this trial developed transient elevation of liver enzymes, likely as a consequence of immune rejection of transduced hepatocytes mediated by AAV capsid-specific CD8(+) T cells. Studies in healthy donors showed that humans carry a population of antigen-specific memory CD8(+) T cells probably arising from wild-type AAV infections. The hypothesis formulated here is that these cells expanded upon re-exposure to capsid, i.e. upon AAV-2 hepatic gene transfer, and cleared AAV epitope-bearing transduced hepatocytes. Other hypotheses have been formulated which include specific receptor-binding properties of AAV-2 capsid, presence of capsid-expressing DNA in AAV vector preparations, and expression of alternative reading frames from the transgene. Absence of a valid animal model has prevented an in-depth mechanistic study of the phenomenon. Several possible solutions to the problem are discussed, including the administration of a short-term anti-T cell immunosuppression regimen concomitant with gene transfer. While more studies will be necessary to further define mechanisms and risks associated with capsid-specific immune responses in humans, monitoring of these responses in clinical trials will be essential to achieving the goal of long-term therapeutic gene transfer in humans.
authors.affiliation: Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Federico
authors.initials: F
authors.lastname: Mingozzi
authors.forename: Katherine A
authors.initials: KA
authors.lastname: High
mesh_terms: D000818:Animals; D001779:Blood Coagulation Factors / Q000235:genetics; D002213:Capsid / Q000276:immunology*; D000229:Dependovirus / Q000235:genetics / Q000276:immunology*; D004285:Dogs; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000009:adverse effects / Q000235:genetics / Q000276:immunology*; D006467:Hemophilia A / Q000628:therapy; D006801:Humans; D007108:Immune Tolerance; D008099:Liver / Q000166:cytology / Q000276:immunology / Q000821:virology; D015201:Meta-Analysis as Topic; D051379:Mice; D023421:Models, Animal; D010322:Parvoviridae Infections / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D035703:Therapies, Investigational / Q000009:adverse effects / Q000639:trends; D019076:Transgenes / Q000276:immunology
chemical_list: D001779:Blood Coagulation Factors