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Impact of the underlying mutation and the route of vector administration on immune responses to factor IX in gene therapy for hemophilia B.
Cao, Ou; Hoffman, Brad E; Moghimi, Babak; Nayak, Sushrusha; Cooper, Mario; Zhou, Shangzhen; Ertl, Hildegund C J; High, Katherine A; Herzog, Roland W.
Afiliação
  • Cao O; Department of Pediatrics, University of Florida, Gainesville, Florida 32610, USA.
Mol Ther ; 17(10): 1733-42, 2009 Oct.
Article em En | MEDLINE | ID: mdl-19603001
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fator IX / Terapia Genética / Hemofilia B / Vetores Genéticos Tipo de estudo: Guideline Limite: Animals / Humans Idioma: En Revista: Mol Ther Assunto da revista: BIOLOGIA MOLECULAR / TERAPEUTICA Ano de publicação: 2009 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fator IX / Terapia Genética / Hemofilia B / Vetores Genéticos Tipo de estudo: Guideline Limite: Animals / Humans Idioma: En Revista: Mol Ther Assunto da revista: BIOLOGIA MOLECULAR / TERAPEUTICA Ano de publicação: 2009 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Estados Unidos