The therapeutic potential of gene transfer as a treatment for retinal disease is promising, yet substantial technical and theoretical problems remain to be solved before this technology can be considered for clinical application. The overall goal of our research effort is to prevent or delay the course of blindness in patients. Our work focuses on the group of inherited blinding diseases called Retinitis Pigmentosa. Currently, there is no widely accepted or effective preventive treatment for this family of retinal degenerations. The goal of this project is to test neurotrophic factors for their ability to """"""""rescue"""""""" photoreceptors from retinal degeneration. Viral vectors derived from adeno-associated virus (AAV) and feline immunodeficiency virus (FIV) will be used for transfer of neurotrophin genes to the retina. Gene transfer methods will be evaluated in several rodent models of retinal degeneration (light damage, RCS, opsin mutations). In these rodent models, cell death is attributed to several different mechanisms. Our underlying premise is that transfer to the retina of neurotrophin genes will protect against cell death, and delay the photoreceptor and RPE loss in retinal degeneration. In previous studies, we established that expression of Neurotrophic factors in the retina could slow the degeneration in rodent models of retinal disease.
In specific aim 1, we propose to optimize the rescue effect of neurotrophic factors and combinations of factors using vectors incorporating inducible promoters to optimize the temporal expression and dose.
In specific aim 2, we will increase the efficiency of retinal gene transfer through modifying the viral tropism of the AAV vector and development of new vectors targeted to specific classes of retinal cells.
In specific aim 3, we will optimize the survival of cone photoreceptors in these disease models using targeted and controlled expression of neurotrophic factors. We will apply the same paradigm of detailed anatomical and functional (ERG) characterization for evaluating the rescue effect that has worked well in previous experiments. In summary, this application supports key, initial """"""""proof-of-principle"""""""" experiments to create retina-specific viral vectors and systems to transfer neurotrophic factors for gene therapy of retinal degeneration.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
3R01EY013533-02S1
Application #
6649517
Study Section
Visual Sciences C Study Section (VISC)
Program Officer
Dudley, Peter A
Project Start
2001-07-01
Project End
2006-05-31
Budget Start
2002-06-01
Budget End
2003-05-31
Support Year
2
Fiscal Year
2002
Total Cost
$425,727
Indirect Cost
Name
University of California Berkeley
Department
Type
Schools of Optometry/Ophthalmol
DUNS #
094878337
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Day, Timothy P; Byrne, Leah C; Schaffer, David V et al. (2014) Advances in AAV vector development for gene therapy in the retina. Adv Exp Med Biol 801:687-93
Geller, Scott F; Ge, Phillip S; Visel, Meike et al. (2008) In vitro analysis of promoter activity in Muller cells. Mol Vis 14:691-705
Guerin, K; Gregory-Evans, C Y; Hodges, M D et al. (2008) Systemic aminoglycoside treatment in rodent models of retinitis pigmentosa. Exp Eye Res 87:197-207
Lee, Edwin S; Flannery, John G (2007) Transport of truncated rhodopsin and its effects on rod function and degeneration. Invest Ophthalmol Vis Sci 48:2868-76
Geller, Scott F; Ge, Phillip S; Visel, Meike et al. (2007) Functional promoter testing using a modified lentiviral transfer vector. Mol Vis 13:730-9
Greenberg, Kenneth P; Geller, Scott F; Schaffer, David V et al. (2007) Targeted transgene expression in muller glia of normal and diseased retinas using lentiviral vectors. Invest Ophthalmol Vis Sci 48:1844-52
Lee, Edwin S; Burnside, Beth; Flannery, John G (2006) Characterization of peripherin/rds and rom-1 transport in rod photoreceptors of transgenic and knockout animals. Invest Ophthalmol Vis Sci 47:2150-60