This program project grant has focused on the use of recombinant adeno-associated virus (rAAV) vector-mediated transduction of hepatocytes as a modality for therapy of genetic diseases. In the first four years of this grant, the investigators in the program have been highly collaborative with each other and have published important proof-of-concept data supporting the use of rAAV vectors for gene therapy of glycogen storage diseases and alpha-1 antitrypsin (AAT) deficiency, as well as key scientific data identifying limitations to rAAV-mediated gene transfer, including host proteins that inhibit rAAV integration (subunits of the DNA-dependent protein kinase, DNA-PK), and immune responses to rAAV vectors and their transgene products that occur in certain contexts. Progress in the field has made available a number of new versions of rAAV vectors, including new serotypes, such as AAV8 vectors, that are now being used within this P01. Overall progress at the University of Florida in the last four years has also been substantial, with the awarding of a new National Gene Vector Laboratory (NGVL) Toxicology Center grant to facilitate formal preclinical toxicology studies and the completion of FDA-Good Manufacturing Practice (GMP) production of a rAAV-AAT vector that is now being used in a phase I clinical trial at UF. In the coming cycle, we intend to exploit all of these advances as well as the recruitment of several new investigators into the program project grant. The new submission will include 4 subprojects: Mechanisms of rAAV vector transduction in the mammalian liver by Dr. Srivastava; Ex vivo transduced liver progenitor cells as a platform for gene therapy by Drs. Song, Berns, and Petersen; Liver-directed Gene Therapy for Alpha-1 antitrypsin (AAT) Deficiency by Dr. Flotte; Liver-based gene therapy for Glycogen Storage Disease by Dr. Byrne. These programs will provide synergy between basic vector virology, advancements in gene transfer technology and disease-oriented translational research. The anticipated outcome of this program is the """"""""spinning off of one or more rAAV8-based liver-directed gene therapy clinical trials, each of which will be submitted individually as a separate new R01 and/or NGVL protocol. Thus, we hope to provide a conduit for the further application of basic and translational science toward the generation of therapeutic products for previously unbeatable genetic diseases.
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