Abstract |
The safety of several gene therapy approaches for treatment of the severe, X-linked bleeding disorder hemophilia is currently being evaluated in early phase clinical trials. One strategy seeks to correct deficiency of functional coagulation factor IX ( hemophilia B) by intramuscular (IM) administration of an adeno-associated viral (AAV) vector. A potentially serious complication of any treatment for hemophilia is formation of inhibitory antibodies against the coagulation factor protein, a risk that increases in the setting of null mutations in the factor IX gene (F9). Here, we describe hemophilia B mice with a large F9 deletion that form inhibitors within 1 to 2 months after IM administration of an AAV vector expressing mouse F9 or after repeated intravenous infusion of mouse F9 concentrate. In both cases, inhibitors are primarily IgG1 immunoglobulins representing a Th2-driven humoral immune response. We further demonstrate that anti-mouse F9 antibody formation in the gene-based approach can be reduced by transient immune modulation at the time of vector administration. Moreover, this maneuver resulted in complete absence of anti-mouse F9 and sustained expression of functional mouse F9 in some hemophilia B mice, particularly in those animals treated with the immunosuppressive drug cyclophosphamide. These data have direct relevance for design of clinical trials and strategies aimed at avoiding immune responses against a secreted transgene product.
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Authors | P A Fields, V R Arruda, E Armstrong, K Chu, F Mingozzi, J N Hagstrom, R W Herzog, K A High |
Journal | Molecular therapy : the journal of the American Society of Gene Therapy
(Mol Ther)
Vol. 4
Issue 3
Pg. 201-10
(Sep 2001)
ISSN: 1525-0016 [Print] United States |
PMID | 11545610
(Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Antibodies
- Immunosuppressive Agents
- RNA, Messenger
- Cyclophosphamide
- Factor IX
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Topics |
- Animals
- Antibodies
(immunology)
- CHO Cells
- Cricetinae
- Cyclophosphamide
(pharmacology)
- Dependovirus
(genetics)
- Factor IX
(administration & dosage, genetics, immunology, therapeutic use)
- Gene Deletion
- Gene Expression
(drug effects)
- Genetic Therapy
(methods)
- Genetic Vectors
(genetics)
- Hemophilia B
(drug therapy, genetics, immunology, therapy)
- Immunosuppressive Agents
(pharmacology)
- Injections, Intramuscular
- Injections, Intravenous
- Mice
- Mice, Inbred C57BL
- Partial Thromboplastin Time
- RNA, Messenger
(genetics, metabolism)
- Risk Factors
- Time Factors
- Transgenes
(genetics)
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