Gene therapy holds great promise for the treatment of various genetic diseases. However, successes in expressing transgenes in vitro are often not reproduced when transferred in vivo. It became clear in several studies that immune responses to the vector and/or transgene product heavily influence in vivo gene therapy oerformance. The Immunology Core has focused its efforts on studying the natural existing T and B cell mmunity to Adenovirus (AdV) and Adeno-associated virus (AAV) in human and non human primates (NHPs). We have also .centered our studies on vector and transgene specific T and B cell responses after systemic or local administration of various rAAV and rAdV serotypes carrying different transgenes in NHP models. This will help us to determine if rAAV and rAdV administration can re-activate existing or induce new T cell responses to the vector or the transgene product, and whether these have any effect on the outcome of the gene therapy and the health of the patient. Moreover we studied the activation of hCFTR-specific T cells in cystic fibrosis mice following gene transfer. The mission of the Immunology Core is to assist Center Participants in developing and conducting assays to evaluate cell mediated and humoral immune responses after gene therapy treatment in small and large animal models including mice, dogs, non human primates and humans. In all these studies we isolated lymphocytes from blood, liver, intestine, primary and secondary lymphoid organs and characterized the T cell response by ex vivo and cultured IFNy ELISPOT, lymphoproliferation assay, in vivo CTL assay, and polychromatic flow cytometric analysis (5-11 colors) of antigen specific T cells. B cell responses were characterized measuring total and neutralizing antibodies in serum and mucosal secretions.

Public Health Relevance

Undesirable immune response to viral vectors and therapeutic gene products could affect the outcome of gene therapy. Immunology Core is well-equipped and determined to investigate this problem in pre-clinical and clinical gene therapy studies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Center Core Grants (P30)
Project #
5P30DK047757-19
Application #
8376146
Study Section
Special Emphasis Panel (ZDK1-GRB-1)
Project Start
Project End
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
19
Fiscal Year
2012
Total Cost
$234,659
Indirect Cost
$85,669
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Gurda, Brittney L; De Guilhem De Lataillade, Adrien; Bell, Peter et al. (2016) Evaluation of AAV-mediated Gene Therapy for Central Nervous System Disease in Canine Mucopolysaccharidosis VII. Mol Ther 24:206-16
Ortved, Kyla; Wagner, Bettina; Calcedo, Roberto et al. (2015) Humoral and cell-mediated immune response, and growth factor synthesis after direct intraarticular injection of rAAV2-IGF-I and rAAV5-IGF-I in the equine middle carpal joint. Hum Gene Ther 26:161-71
Bissig-Choisat, Beatrice; Wang, Lili; Legras, Xavier et al. (2015) Development and rescue of human familial hypercholesterolaemia in a xenograft mouse model. Nat Commun 6:7339
Wang, Lili; Bell, Peter; Somanathan, Suryanarayan et al. (2015) Comparative Study of Liver Gene Transfer With AAV Vectors Based on Natural and Engineered AAV Capsids. Mol Ther 23:1877-87
Calcedo, Roberto; Franco, Judith; Qin, Qiuyue et al. (2015) Preexisting Neutralizing Antibodies to Adeno-Associated Virus Capsids in Large Animals Other Than Monkeys May Confound In Vivo Gene Therapy Studies. Hum Gene Ther Methods 26:103-5
Baek, Jeong-In; Choi, Soo Young; Chacon-Heszele, Maria F et al. (2014) Expression of Drosophila forkhead transcription factors during kidney development. Biochem Biophys Res Commun 446:15-7
O'Neill, S M; Hinkle, C; Chen, S-J et al. (2014) Targeting adipose tissue via systemic gene therapy. Gene Ther 21:653-61
Huang, Liwei; Xiao, An; Wecker, Andrea et al. (2014) A possible zebrafish model of polycystic kidney disease: knockdown of wnt5a causes cysts in zebrafish kidneys. J Vis Exp :
Huang, Liwei; Xiao, An; Choi, Soo Young et al. (2014) Wnt5a is necessary for normal kidney development in zebrafish and mice. Nephron Exp Nephrol 128:80-8
Adam, Virginie S; Crosariol, Marco; Kumar, Sachin et al. (2014) Adeno-associated virus 9-mediated airway expression of antibody protects old and immunodeficient mice against influenza virus. Clin Vaccine Immunol 21:1528-33

Showing the most recent 10 out of 222 publications