Pediatrics

Research Overview

My research program seeks to develop a gene therapy for the X-linked bleeding disorder hemophilia and to establish prophylactic immune tolerance protocols for treatment of genetic diseases. Severe hemophilia is characterized by frequent spontaneous bleeding. Our work in canine hemophilia has shown that gene therapy can permanently correct this defect, and clinical trials have been ongoing to translate these successes to treatment of humans. Treatment is only successful of the functional therapeutic protein expressed by the donated gene is not rejected by the immune system. Using interdisciplinary approaches and collaborations, my lab is pursuing several alternative strategies to induce and maintain tolerance to therapeutic proteins (such as hepatic gene transfer, mucosal tolerance, and immune modulation) in gene- and protein-based therapies. An important mechanistic aspect of these studies is to understand the role of immune regulation. For example, we found that hepatic gene transfer with adeno-associated viral vectors can induce antigen-specific tolerance to coagulation factors and other proteins, which depends on activation of regulatory T cells (CD4+CD25+FoxP3+ T cells). These cells are able to suppress cytotoxic T lymphocyte responses and antibody formation after adoptive transfer in murine models of gene therapy for hemophilia (see Curr. Gene Ther. 7: 381-390, 2007). Another important aspect of our research is to understand the role of the target organ of gene transfer or antigen administration on immune responses (organ-specific immunity). Finally, we are using small and large animal models of hemophilia to advance basic science toward clinical application. Collaborators in the Dept. Pediatrics include Drs. Arun Srivastava and Barry Byrne.

About

Dr. Herzog received a Ph.D. in Microbiology from Auburn University in 1996. He subsequently performed postdoctoral research in gene therapy/hematology at the Children's Hospital of Philadelphia, and became Assistant Professor of Pediatrics at the University of Pennsylvania in 2000. In 2005, he joined the University of Florida as an Associate Professor. Dr. Herzog's research has received multiple awards, including a plenary presentation at the annual meeting of the American Society of Hematology (1998), a career development award from the National Hemophilia Foundation (2000), an outstanding investigator award from the American Society of Gene Therapy (ASGT, 2003), and a Bayer Hemophilia Award (2007). He has served as chair of the ASGT immunology and education committees and as a board member of several gene therapy journals. He is currently editing two textbooks in gene therapy. His laboratory has received multiple grants from the NIH and other funding agencies, and several of his trainees have also obtained fellowships and awards for their research.

Key Publications

Additional publications can be found in PubMed.

1. Zhong L, Li B, Mah CS, Govindasamy L, Agbandje-McKenna M, Mario Cooper M, Herzog RW, Zolotukhin I, Warrington, Jr. KH, Weigel-Van Aken KA, Hobbs JA, Zolotukhin S, Muzyczka N, Srivastava A (2008) Next generation of adeno-associated virus 2 vectors: Point mutations in tyrosines lead to high-efficiency transduction at lower doses. Proc Natl Acad Sci USA 22: 7827-7832
2. Hoffman BE, Dobrzynski E, Wang L, Hirao L, Mingozzi F, Cao O, Herzog RW (2007) Skeletal muscle as a target for supplementary factor IX gene transfer. Hum. Gene Ther. 18: 603-613 [cover article]
3. Cao O, Dobrzynski E, Wang L, Nayak S, Mingle B, Terhorst CP, Herzog RW (2007) Induction and role of regulatory CD4+CD25+ T cells in tolerance to the transgene product following hepatic in vivo gene transfer. Blood 110: 1132-1140
4. Cao O, Armstrong E, Schlachterman A, Wang L, Okita DK, Conti-Fine B, High KA, Herzog RW (2006) Immune deviation by mucosal antigen administration suppresses gene transfer-induced inhibitor formation to factor IX. Blood 108: 480-486
5. Dobrzynski E, Fitzgerald JC, Cao O, Mingozzi F, Wang L, Herzog RW (2006) Prevention of cytotoxic T lymphocyte responses to factor IX expressing hepatocytes by gene transfer-induced regulatory T cells. Proc Natl Acad Sci USA 103: 4592-4597