The major morbidity of congenital factor Vlll and IX deficiencies (hemophilia A and B) is the progressive crippling arthropathy caused by repeated joint bleeding. The institution early in childhood of prophylactic intravenous factor Vlll or IX replacement throughout the circulation can prevent bleeding-induced joint damage. Apparent clinical success in some subjects receiving a liver-directed factor IX adeno-associated virus (AAV) gene therapy vector raises hope. Nevertheless, failed expression in other subjects receiving identical doses suggests the promise of this strategy may be limited to a select group of individuals, specifically, those without preexisting neutralizing antibodies against AAV;in addition, individuals having neutralizing antibodies against the clotting factor transgene and those with significant liver disease are excluded. The proposed investigations exploit the finding that neutralizing antibody titers appear lower in the hemophilic joint than in the circulation, and the studies explore the potential for local clotting factor gene delivery in the joint to decrease morbidity for hemophilic individuals not adequately treated by available prophylactic protein or emerging gene therapies. The studies compare phylogenetically distinct AAV serotypes for localized gene expression in joint synovial fibroblasts versus chondrocytes in nonnal and blood-damaged joints. Optimization of factor IX vectors having wild type or gain of function genes will he pursued in hemophilic mice, as well as evaluation of comparative immunogenicity of these variants in novel hemophilia B mouse models carrying both human hemophilia gene sequences and human MHC II haplotype. Intraarticular gene delivery following passive transfer of/^AV-neutralizing antibodies from AAV- immunized mice and dogs will be studied in these small and large hemophilia models. The FIX studies will inform evaluation of wild-type and mutant factor Vlll vectors delivered with adjuvant proteasome inhibitors for joint expression in hemophilia A mice in the setting of induced factor Vlll inhibitors or AAV-neutralizing antibodies. The broad objective of the studies is to advance tools for the study of blood-induced joint damage and examine therapies to circumvent major limitations imposed by systemic humoral immunity.
The potential to harness naturally-occurring viaises to correct disease can be hampered by antibodies that circulate in the blood and prevent potentially curative gene delivery. In conditions causing localized damage, such as the hemophilia's joint destruction, avoiding treatment of the entire body may be an effective and safe way to decrease the burden of disease. The studies pursue efficient strategies to avoid antibodies and improve living with hemophilia by targeting therapy directly to joints.
|Chai, Zheng; Samulski, R Jude; Li, Chengwen (2018) Nab Escaping AAV Mutants Isolated from Mouse Muscles. Bio Protoc 8:|
|Sun, Junjiang; Shao, Wenwei; Chen, Xiaojing et al. (2018) An Observational Study from Long-Term AAV Re-administration in Two Hemophilia Dogs. Mol Ther Methods Clin Dev 10:257-267|
|Chai, Zheng; Zhang, Xintao; Rigsbee, Kelly Michelle et al. (2018) Cryoprecipitate augments the global transduction of the adeno-associated virus serotype 9 after a systemic administration. J Control Release 286:415-424|
|Tse, Longping V; Moller-Tank, Sven; Meganck, Rita M et al. (2018) Mapping and Engineering Functional Domains of the Assembly-Activating Protein of Adeno-associated Viruses. J Virol 92:|
|Albright, Blake H; Storey, Claire M; Murlidharan, Giridhar et al. (2018) Mapping the Structural Determinants Required for AAVrh.10 Transport across the Blood-Brain Barrier. Mol Ther 26:510-523|
|Berry, Garrett E; Tse, Longping V (2017) Virus Binding and Internalization Assay for Adeno-associated Virus. Bio Protoc 7:|
|Tse, Longping Victor; Klinc, Kelli A; Madigan, Victoria J et al. (2017) Structure-guided evolution of antigenically distinct adeno-associated virus variants for immune evasion. Proc Natl Acad Sci U S A 114:E4812-E4821|
|Liang, Katharine J; Woodard, Kenton T; Weaver, Mark A et al. (2017) AAV-Nrf2 Promotes Protection and Recovery in Animal Models of Oxidative Stress. Mol Ther 25:765-779|
|Wang, M; Sun, J; Crosby, A et al. (2017) Direct interaction of human serum proteins with AAV virions to enhance AAV transduction: immediate impact on clinical applications. Gene Ther 24:49-59|
|Chai, Zheng; Sun, Junjiang; Rigsbee, Kelly Michelle et al. (2017) Application of polyploid adeno-associated virus vectors for transduction enhancement and neutralizing antibody evasion. J Control Release 262:348-356|
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