title: Impact of the underlying mutation and the route of vector administration on immune responses to factor IX in gene therapy for hemophilia B.
abstract: Immune responses to factor IX (F.IX), a major concern in gene therapy for hemophilia, were analyzed for adeno-associated viral (AAV-2) gene transfer to skeletal muscle and liver as a function of the F9 underlying mutation. Vectors identical to those recently used in clinical trials were administered to four lines of hemophilia B mice on a defined genetic background [C3H/HeJ with deletion of endogenous F9 and transgenic for a range of nonfunctional human F.IX (hF.IX) variants]. The strength of the immune response to AAV-encoded F.IX inversely correlated with the degree of conservation of endogenous coding information and levels of endogenous antigen. Null mutation animals developed T- and B-cell responses in both protocols. However, inhibitor titers were considerably higher upon muscle gene transfer (or protein therapy). Transduced muscles of Null mice had strong infiltrates with CD8+ cells, which were much more limited in the liver and not seen for the other mutations. Sustained expression was achieved with liver transduction in mice with crm(-) nonsense and missense mutations, although they still formed antibodies upon muscle gene transfer. Therefore, endogenous expression prevented T-cell responses more effectively than antibody formation, and immune responses varied substantially depending on the protocol and the underlying mutation.
authors: Department of Pediatrics, University of Florida, Gainesville, Florida 32610, USA.
authors: Ou
authors: O
authors: Cao
authors: Brad E
authors: BE
authors: Hoffman
authors: Babak
authors: B
authors: Moghimi
authors: Sushrusha
authors: S
authors: Nayak
authors: Mario
authors: M
authors: Cooper
authors: Shangzhen
authors: S
authors: Zhou
authors: Hildegund C J
authors: HC
authors: Ertl
authors: Katherine A
authors: KA
authors: High
authors: Roland W
authors: RW
authors: Herzog
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005164:Factor IX / Q000235:genetics / Q000276:immunology*; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics*; D002836:Hemophilia B / Q000628:therapy*; D006801:Humans; D056724:Immunity, Humoral / Q000235:genetics / Q000276:immunology; D007150:Immunohistochemistry; D051379:Mice; D008856:Microscopy, Fluorescence; D009154:Mutation; D020125:Mutation, Missense
chemical_list: D005164:Factor IX