Cone photoreceptors are responsible for central visual acuity, color vision, and photopic vision and are therefore critical for visual performance in daily human life. As such, it is of utmost importance to target cones when designing therapeutic treatment for retinal diseases such as achromatopsia, cone dystrophies, and cone-rod dystrophies that primarily affect cones. However, cone rescue is of even greater importance in diseases where cones are affected secondarily, such as in retinitis pigmentosa (RP) and most forms of age-related macular degeneration (AMD), the leading cause of vision loss in people over 65 years of age. The overarching aim of this proposal is to develop 2 natural canine achromatopsia models as a platform for recombinant adeno-associated virus (rAAV)-mediated cone-directed gene therapy. In both canine models, loss-of-function mutations in the cone cyclic nucleotide-gated channel beta subunit (CNGB3) lead to a disease phenotype identical to human achromatopsia. Mutations in CNGB3 are the most common cause for achromatopsia in man, making the 2 canine strains the optimal animal model in which to carry out cone-targeted gene replacement studies with translational potential. The long-term success of rAAV-mediated retinal gene therapy for primary defects of the retinal pigment epithelium (RPE) has been demonstrated in several species, including dogs. Because of their successful, stable, and apparently safe transgene expression, these studies are now in Phase 1 clinical trials. In contrast to RPE defects, the treatment of primary photoreceptor diseases is more difficult, and previous gene therapy studies have shown variable success. The hypothesis to be tested in this proposal is that cone function and structure can be restored, and degeneration prevented, using rAAV-mediated cone-directed delivery of wildtype CNGB3 cDNA under control of cone-specific promoters. To test this hypothesis, we specifically propose to 1) optimize rAAV vectors for targeted gene expression in cones and 2) maximize preservation of cone function following cone-specific expression of CNGB3 cDNA in the two canine models. Results from the first two aims will provide data regarding the efficiency, safety, and limitations of the treatment. In the final aim, functional, structural, and molecular disease correlates of the canine CNGB3 mutations will be characterized and their potential reversal following successful gene therapy assessed in order to more fully understand disease mechanisms and to provide disease metrics for establishing an optimal therapeutic time window. The canine achromatopsia models offer unique opportunities for proof-of-principle of cone-directed gene therapy and for eventual translation to patients.

Public Health Relevance

The cone photoreceptors in the retina are responsible for day- and color vision. These cones are lost in many diseases of the retina which lead to severe vision deficit and even blindness. This research proposal focuses on the development of a new gene therapy to recover diseased cones and their function and to restore day-vision

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY019304-05
Application #
8446968
Study Section
Special Emphasis Panel (ZRG1-CB-G (90))
Program Officer
Shen, Grace L
Project Start
2009-02-01
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2015-01-31
Support Year
5
Fiscal Year
2013
Total Cost
$398,450
Indirect Cost
$120,757
Name
Michigan State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
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Guziewicz, Karina E; Zangerl, Barbara; Komaromy, Andras M et al. (2013) Recombinant AAV-mediated BEST1 transfer to the retinal pigment epithelium: analysis of serotype-dependent retinal effects. PLoS One 8:e75666
Cideciyan, Artur V; Jacobson, Samuel G; Beltran, William A et al. (2013) Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement. Proc Natl Acad Sci U S A 110:E517-25
Garcia, Monique M; Ying, Gui-shuang; Cocores, Christina A et al. (2010) Evaluation of a behavioral method for objective vision testing and identification of achromatopsia in dogs. Am J Vet Res 71:97-102
Komaromy, Andras M; Alexander, John J; Rowlan, Jessica S et al. (2010) Gene therapy rescues cone function in congenital achromatopsia. Hum Mol Genet 19:2581-93