This proposal evaluates the translational potential of optogenetic therapy, an approach whereby visual function is achieved through the use of a molecular prosthesis that transmits its signals to downstream visual circuits. Studies in vitro and in vivo in animal models by our collaborators (and others) have demonstrated that light-activated chloride pumps or channels can be introduced into specific retinal cell types in diseased or atrophic retinas. There, these molecular prostheses can permit visual responses where before, there were none. The present program aims to address the knowledge gaps and technical limitations relevant to development of optogenetic therapy in two different paradigms: 1) Physiologically optimized forms of Halorhodopsin (NpHR) will be used to activate function of failing cone photoreceptors after the rod photoreceptors have degenerated;2) Optimized Channelrhodopsins (ChRd) will be used to confer light responsiveness to second order retinal neurons in degenerated retinas. We will design and develop the appropriate vectors, delivery strategies and outcome measures for each paradigm, will carry out the prerequisite preclinical safety and efficacy studies, and will bring one of the studies (NpHR) to clinical trial. In the process, novel strategies of altering the transduction characteristics of adeno-associated virus (AAV) will be developed, new surgical approaches which could be applied to human eyes will be devised, and sensitive, noninvasive, clinically relevant outcome measures will be defined. Simultaneous with development of the technology, we will evaluate the bioethics of gene therapy-mediated delivery of molecular prostheses in humans. This comprehensive program benefits greatly from the wisdom and experience of many talented collaborators and advisors and takes advantage of the infrastructure that the PI has already developed for ocular gene therapy translational research. Successful application of optogenetic therapy will expand the number of disease targets that are potentially treatable by gene therapy dramatically. It will change the number of retinal gene therapy targets from the realm of isolated orphan diseases to conditions that are epidemic in nature. In addition, the reagents, strategies and technical advances developed in this project will be useful for many other ocular and extra-ocular applications. Finally, not only could the results from this project lead to a significant improvement in the quality of life for millions of individuals, but they could also pave the way for development of novel gene therapy approaches for the treatment of other devastating sensorineural diseases.

Public Health Relevance

Development of a novel optogenetic approach to restore visual function to blind individuals could potentially be applicable to a large number (>3 million) of individuals suffering from inherited and acquired forms of blindness. This includes an estimated 1.75 million Americans with advanced agerelated macular degeneration (AMD), 50-100,000 Americans with retinitis pigmentosa, 1 million Americans blind due to complications of diabetic retinopathy, an estimated 500 babies/year blinded by retinopathy of prematurity, and individuals unable to take advantage of effective treatments for traumatic retinal detachment in a timely fashion (i.e., individuals injured during combat or in remote locations). In addition, the proposed research will develop an entirely new set of reagents (and knowledge about the properties and safety of these reagents) which will expand the toolkit for ocular and extra-ocular gene therapy.

National Institute of Health (NIH)
National Eye Institute (NEI)
NIH Director’s Pioneer Award (NDPA) (DP1)
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Special Emphasis Panel (ZGM1-NDPA-A (01))
Program Officer
Shen, Grace L
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University of Pennsylvania
Schools of Medicine
United States
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Carvalho, Livia S; Vandenberghe, Luk H (2015) Promising and delivering gene therapies for vision loss. Vision Res 111:124-33
Ashtari, Manzar; Cyckowski, Laura; Yazdi, Alborz et al. (2014) fMRI of retina-originated phosphenes experienced by patients with Leber congenital amaurosis. PLoS One 9:e86068
Zinn, Eric; Vandenberghe, Luk H (2014) Adeno-associated virus: fit to serve. Curr Opin Virol 8:90-7
Simonato, Michele; Bennett, Jean; Boulis, Nicholas M et al. (2013) Progress in gene therapy for neurological disorders. Nat Rev Neurol 9:298
Simonato, Michele; Bennett, Jean; Boulis, Nicholas M et al. (2013) Progress in gene therapy for neurological disorders. Nat Rev Neurol 9:277-91