All ETDs from UAB

Advisory Committee Chair

David G Standaert

Advisory Committee Members

Scott R Barnum

David M Bedwell

J Michael Wyss

Document Type

Dissertation

Date of Award

2012

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Parkinson disease (PD) is a devastating movement disorder affecting between 500,000 and 1,000,000 individuals in the United States alone, and for which there is currently no cure. Therapies such as dopamine replacement help initially, but with disease progression these lose efficacy and do not alter the underlying degenerative process. Gene therapy is the delivery of exogenous genetic material to correct an underlying disorder. A major advantage of this approach is the ability to distribute potent therapies to specific targets over an extended duration, properties necessary for the treatment of progressive degenerative diseases such as PD. A number of clinical trials of gene therapy in PD have been undertaken providing proof of safety, but none have resulted in better efficacy than best medical therapy. Although the promise of a gene therapy that slows or reverses PD progression continues to drive innovation, rigorous standards must be met in order to insure the safety of exogenous viral-based gene therapy delivery to humans in clinical trials. A vector platform capable of delivering current and future therapeutics in a targeted manner--particularly to neurons--would ease this burden. Such a platform must be capable of targeted gene delivery as well as a large genetic capacity so payloads are not limited. Adenovirus vectors offer the flexibility of capsid-incorporated targeting modifications (transductional targeting) and contain a large genome (36 kilobases) for nearly unrestricted combinations of transcriptional targeting, multiple transgenes, and future control elements. In this Dissertation, we describe the development of a novel neuron-targeted adenovirus based gene therapy vector that can serve as such a platform. We begin by understanding the targeting profile of unmodified adenovirus serotype 5 (Ad5) vectors in the CNS, and show Ad5 can infect neuronal cells in a receptor-independent manner. We next screen transductionally modified Ad vectors against neuron cell lines in vitro to predict neuronal tropism in vivo. Finally, we develop a novel fiber-modified Ad vector to assess the in vitro results in the intact murine CNS, and find the in vitro predictions borne out, with CK2-CGW vector providing selective gene expression in neuronal cells while detargeting non-neuronal cells.

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