The overall theme of this competitive renewal application is to characterize immune responses induced upon gene transfer by adeno-associated virus (AAV) vectors and to devise avenues to circumvent effector Immune responses that impede sustained gene transfer. In its 1(r)'objective, the program will analyze T cell responses to the capsid antigens of AAV vectors pseudotyped with capsids of different serotypes or with genetically modified capsids using in vitro systems, experimental animals and samples from human subjects to assess functionality of T cells induced by natural infections or AAV gene transfer and to determine the longevity of T cell responses to the latter. Avenues to circumvent destructive T cell responses to AAV gene transfer including capsid modifications and pharmacological interventions will be explored. In its 2"" objective, the program will analyze T cell responses to the transgene product of AAV vectors with focus on double-stranded AAV vectors that according to preliminary data of the program elicit more potent innate and adaptive immune responses than single-stranded AAV vectors. In its 3"^ objective, the program will explore the use of regulatory T cells (Tregs) to suppress destructive immune responses against AAV capsid or therapeutic proteins such as clotting factors to prevent a primary response to gene transfer or to down-regulate an existing response to AAV-mediated gene transfer or protein therapy. The program is divided into 3 Projects supported by 2 Cores. Project 1 (KA High): Immune Responses to Capsid in AAV-Mediated Gene Transfer Project 2 (HC ErtI): T Cells to AAV and AAV-Encoded Transgene Products Project 3 (RW Herzog, C Terliorst): Pathways Towards Immune Tolerance to Coagulation Factors Core A (HC ErtI): Administrative Core Core B (S Zliou): Vector Core

Agency
National Institute of Health (NIH)
Type
Research Program Projects (P01)
Project #
5P01HL078810-10
Application #
8690940
Study Section
Heart, Lung, and Blood Program Project Review Committee (HLBP)
Program Officer
Link, Rebecca P
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Wistar Institute
Department
Type
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Rogers, Geoffrey L; Martino, Ashley T; Zolotukhin, Irene et al. (2014) Role of the vector genome and underlying factor IX mutation in immune responses to AAV gene therapy for hemophilia B. J Transl Med 12:25
Sarkar, Debalina; Biswas, Moanaro; Liao, Gongxian et al. (2014) Ex Vivo Expanded Autologous Polyclonal Regulatory T Cells Suppress Inhibitor Formation in Hemophilia. Mol Ther Methods Clin Dev 1:
Wang, Xiaomei; Moghimi, Babak; Zolotukhin, Irene et al. (2014) Immune tolerance induction to factor IX through B cell gene transfer: TLR9 signaling delineates between tolerogenic and immunogenic B cells. Mol Ther 22:1139-50
Liao, Gongxian; van Driel, Boaz; Magelky, Erica et al. (2014) Glucocorticoid-induced TNF receptor family-related protein ligand regulates the migration of monocytes to the inflamed intestine. FASEB J 28:474-84
Liao, Gongxian; O'Keeffe, Michael S; Wang, Guoxing et al. (2014) Glucocorticoid-Induced TNF Receptor Family-Related Protein Ligand is Requisite for Optimal Functioning of Regulatory CD4(+) T Cells. Front Immunol 5:35
Wu, Te-Lang; Li, Hua; Faust, Susan M et al. (2014) CD8+ T cell recognition of epitopes within the capsid of adeno-associated virus 8-based gene transfer vectors depends on vectors' genome. Mol Ther 22:42-51
Sherman, Alexandra; Schlachterman, Alexander; Cooper, Mario et al. (2014) Portal vein delivery of viral vectors for gene therapy for hemophilia. Methods Mol Biol 1114:413-26
Mingozzi, Federico; Anguela, Xavier M; Pavani, Giulia et al. (2013) Overcoming preexisting humoral immunity to AAV using capsid decoys. Sci Transl Med 5:194ra92
Buchlis, George; Odorizzi, Pamela; Soto, Paula C et al. (2013) Enhanced T cell function in a mouse model of human glycosylation. J Immunol 191:228-37
Mingozzi, Federico; High, Katherine A (2013) Immune responses to AAV vectors: overcoming barriers to successful gene therapy. Blood 122:23-36

Showing the most recent 10 out of 51 publications