Cone Targeted Gene Therapy

October 5, 2011 -
11:45am to 1:45pm

The Fox Center for Vision Restoration organizes an exciting lecture series focusing on ocular regeneration and new therapies.

Distinguished national and international speakers present their innovative and multidisciplinary approaches to finding cures for vision impairment. The objective of this lecture series is to accelerate research through knowledge sharing, partnership building and out of the box thinking.

The lecture series should be of interest to:
* clinicians with an interest in ophthalmology
* scientists and engineers interested in tissue engineering, cellular therapies and assistive technologies
* students, postdoctoral fellows, residents, nurses and research staff

William W. Hauswirth, PhD
Rybaczki-Bulard Professor of Ophthalmology
University of Florida College of Medicine

Dr. Hauswirth received his B.S. in Chemistry from Stanford University and his Ph.D in Physical Chemistry from Oregon State University. After an NIH Fellowship in the Biochemistry Department at Johns Hopkins University, he joined that department as an Assistant Professor. In 1976, he joinedWilliam Hauswirth the faculty of Molecular Genetics and in 1985 the Ophthalmology faculty at the University of Florida.

While at UF Dr. Hauswirth is, in part, responsible for determining the mechanism of replication of adeno-associated virus (AAV) DNA and the discovery of mitochondrial DNA heteroplasmy in mammals. More recently he collaborated on the first successful rescue of a dominant genetic disease in animals (ribozyme treatment in a Retinitis Pigmentosa model) and the first restoration of vision for a recessive retinal disease. His current interests involve the delivery and testing of potentially therapeutic genes for Retinitis Pigmentosa, Macular Degeneration, Diabetic Retinopathy and Glaucoma in natural and transgenic animal models of each human disease.

Dr. Hauswirth is principal investigator on numerous NIH and private foundation grants supporting this work, including a 3-University consortium grant that funds the pre-clinical stages of a gene therapy trial for LCA, a severe form of congenital early childhood blindness. He is also CO-PI on a related clinical trial grant for LCA2.

In collaboration with Genzyme Corp. and AGTC, Inc, he is developing a gene-based therapy for the wet form of AMD, with the first patients expected in early-mid 2008. Finally, he collaborates with more than 70 PI’s around the world, primarily by designing and providing them, free of charge, AAV vectors (~125 per year) for disorders affecting essentially all parts of the eye.

Dr. Hauswirth has authored over 175 articles and reviews and has frequently served as a member of several different NIH/NEI Study Sections. He has also served as either a permanent or ad hoc member of research panels for other NIH Institutes, NSF, USDA, National Geographic Society, the American Heart Association and the Foundation Fighting Blindness, as well as consulted on research grants for the United Kingdom, France, Italy, Japan, Belgium, Denmark, Finland and Kuwait. He is currently on the Scientific Boards of The Foundation Fighting Blindness and the Macula Vision Research Foundation.

Over the past fifteen years Dr. Hauswirth has received short-term (3-month) professorships from Oxford University, University of Edinburgh, University of Paris, and University of Pavia, and is currently on the editorial boards of several vision journals. He was recently awarded the 2001 Alcon Award for Vision Research, the 2002 Foundation Fighting Blindness Trustees Award, the 2004 John Kayser International Award for Retinal Research, the 2005 Scientist of the Year from the Hope Foundation and has received the University of Florida Distinguished Research Award twice.

Presentation abstract

We sought to validate the generality and efficacy of strategy for AAV vector mediated, cone targeted gene therapy.
For this purpose we tested therapeutic outcomes upon delivering the corresponding wild type cDNA to retinas of a variety of preclinical models in which:
1. the retinal disease affected only cones
2. the genetics were well established in the human disease counterpart
3. the animal model mimicked the human phenotype
4. there would be a clear clinical endpoint(s) for a treatment trial.
Cone targeted gene replacement therapy has been evaluated in several preclinical models. In every case:
1. the AAV vector targeted therapeutic gene expression to cones
2. cone-mediated ERG amplitudes were restored, in several cases to near normal
3. cone mediated, light-elicited behavior was significantly improved.

Additionally, we have begun to explore the behavior of AAV vector variants containing site directed mutations in surface exposed tyrosine residues in retinas in order to develop a vitreal method of delivering therapeutic genes to foveal cones that avoids the foveal detachment associated with subretinal vector delivery.  The current status of this effort will be summarized.