New Approaches for Therapeutic Gene Transfer and Genome Editing In Vivo

Date: 
Feb 9 2017 - 12:00pm
Location: 
Pavilion A Auditorium
Event Category: 
Dean’s Distinguished Lecture Series
Speaker: 
Mark A. Kay, MD, PhD
Institute: 
Stanford University

My laboratory has long been interested in the development of gene transfer vectors for gene therapy as well as manipulating non-coding RNAs for therapeutic purposes. A major interest has been in unraveling the mechanism of viral vector transduction in vivo. Our work during the last 15 years has focused on two vector systems, mini-circles and recombinant AAVs (rAAV). We have shown that DNA vectors consisting of a circularized eukaryotic expression cassette (lacking plasmid DNA backbone sequences) provide more persistent levels of transgene expression from quiescent tissues compared to the same plasmid vectors. We recently developed a rapid mini-circle production methodology allowing any molecular biologist to make these vectors. Moreover, we have evidence that differential chromatinization of these DNAs plays a role in their expression profiles. Our extensive work using rAAV vectors played a critical role in our human factor IX clinical trial that was the first systemic administration of rAAV into humans. My laboratory has been a leader in developing DNA shuffling approaches for the creation of novel AAV vectors with useful transduction properties. Using gene transfer vectors, we studied the potential of using transcriptional-based RNAi to treat human disease. Our work uncovered key mechanistic insights into how non-coding miRNAs are loaded into active RISC complexes in mammals as well as the discovery of new classes of small RNAs derived from tRNA, and non-coding RNAs that may be generated by RNA-directed RNA transcription in vertebrates. Some of the main RNAi accomplishments include: the first demonstration of RNAi activity in whole non-embryonic mammals, inhibition of human viral (HBV) replication in whole animals and demonstration of toxicity due to shRNA.

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