The goal of this application is to further characterize immune responses that can cause the elimination of recombinant adeno-associated virus (rAAV) transduced cells. Most humans are naturally exposed to AAV-2 together with a helper virus and thus have immunological memory to AAV-2. Memory T cells can be triggered more readily than naive lymphocytes, which was not taken into account by pre-clinical animal experiments conducted thus far. Concerns about immunological consequences of rAAV-mediated gene transfer were substantiated by the outcome of a clinical trial in which human hemophilia B patients were infused into the liver with rAAV-2-F.IX vectors. Only one patient achieved therapeutic levels of F.IX, which were sustained for 4 weeks and then started to decline. At the same time the patient developed a transaminitis, which resolved after F.IX levels decreased to baseline levels. Overall, the patient's clinical course was compatible with immune-mediated destruction of rAAV-transduced hepatocytes. Additional data generated since substantiated our hypothesis that AAV-2-specific T cells induced by a natural infection can cause elimination of rAAV-transduced hepatocytes. To further define immune responses to AAV and rAAV-encoded transgenes under conditions thai mimic those of human hemophilia patients and to then devise informed strategies to circumvent such problems we are proposing 4 interlinked Projects supported by 2 Cores. Project 1 will define T cell responses to AAV capsid proteins in humans and in non-human primates and assess their effect on hepatic rAAV-mediated gene transfer. Project 2 will elucidate the effect of pre-existing AAV-2-specific T cell-mediated immunity on hepatic rAAV vector-mediated gene transfer in mice. Project 3 will define regulatory immune responses that prevent induction of CD8+ T cell responses to a rAAV-encoded transgene product. Project 4 will focus on the potential use of regulatory T cells to ablate unwanted immune responses to rAAV-mediated gene transfer. The projects will be supported by an Administrative Core, which will provide the needed oversight, and a Vector Core, which will provide the investigators with purified and quality controlled vectors.
| High, Katherine A; Anguela, Xavier M (2016) Adeno-associated viral vectors for the treatment of hemophilia. Hum Mol Genet 25:R36-41 |
| Vercauteren, Koen; Hoffman, Brad E; Zolotukhin, Irene et al. (2016) Superior In vivo Transduction of Human Hepatocytes Using Engineered AAV3 Capsid. Mol Ther 24:1042-1049 |
| Wang, Xiaomei; Terhorst, Cox; Herzog, Roland W (2016) In vivo induction of regulatory T cells for immune tolerance in hemophilia. Cell Immunol 301:18-29 |
| Sharma, Rajiv; Anguela, Xavier M; Doyon, Yannick et al. (2015) In vivo genome editing of the albumin locus as a platform for protein replacement therapy. Blood 126:1777-84 |
| Biswas, Moanaro; Terhorst, Cox; Herzog, Roland W (2015) Treg: tolerance vs immunity. Oncotarget 6:19956-7 |
| Biswas, Moanaro; Sarkar, Debalina; Kumar, Sandeep R P et al. (2015) Synergy between rapamycin and FLT3 ligand enhances plasmacytoid dendritic cell-dependent induction of CD4+CD25+FoxP3+ Treg. Blood 125:2937-47 |
| Rogers, Geoffrey L; Suzuki, Masataka; Zolotukhin, Irene et al. (2015) Unique Roles of TLR9- and MyD88-Dependent and -Independent Pathways in Adaptive Immune Responses to AAV-Mediated Gene Transfer. J Innate Immun 7:302-14 |
| Rogers, Geoffrey L; Herzog, Roland W (2015) Gene therapy for hemophilia. Front Biosci (Landmark Ed) 20:556-603 |
| Hui, Daniel J; Edmonson, Shyrie C; Podsakoff, Gregory M et al. (2015) AAV capsid CD8+ T-cell epitopes are highly conserved across AAV serotypes. Mol Ther Methods Clin Dev 2:15029 |
| Wang, Xiaomei; Su, Jin; Sherman, Alexandra et al. (2015) Plant-based oral tolerance to hemophilia therapy employs a complex immune regulatory response including LAP+CD4+ T cells. Blood 125:2418-27 |
Showing the most recent 10 out of 74 publications
