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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
NIH Director’s Pioneer Award (NDPA) (DP1)
Project #
5DP1EY023177-04
Application #
8711469
Study Section
Special Emphasis Panel (ZGM1-NDPA-A (01))
Program Officer
Shen, Grace L
Project Start
2011-09-30
Project End
2016-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
4
Fiscal Year
2014
Total Cost
$650,000
Indirect Cost
$243,750
Name
University of Pennsylvania
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Ashtari, Manzar; Zhang, Hui; Cook, Philip A et al. (2015) Plasticity of the human visual system after retinal gene therapy in patients with Leber's congenital amaurosis. Sci Transl Med 7:296ra110
Sochor, Matthew A; Vasireddy, Vidyullatha; Drivas, Theodore G et al. (2015) An Autogenously Regulated Expression System for Gene Therapeutic Ocular Applications. Sci Rep 5:17105
Carvalho, Livia S; Vandenberghe, Luk H (2015) Promising and delivering gene therapies for vision loss. Vision Res 111:124-33
Cheever, Thomas R; Berkley, Dale; Braun, Serge et al. (2015) Perspectives on best practices for gene therapy programs. Hum Gene Ther 26:127-33
Vandenberghe, Luk H (2015) What Is Next for Retinal Gene Therapy? Cold Spring Harb Perspect Med 5:
Drivas, Theodore G; Wojno, Adam P; Tucker, Budd A et al. (2015) Basal exon skipping and genetic pleiotropy: A predictive model of disease pathogenesis. Sci Transl Med 7:291ra97
Zinn, Eric; Pacouret, Simon; Khaychuk, Vadim et al. (2015) In Silico Reconstruction of the Viral Evolutionary Lineage Yields a Potent Gene Therapy Vector. Cell Rep 12:1056-68
Minella, A L; Mowat, F M; Willett, K L et al. (2014) Differential targeting of feline photoreceptors by recombinant adeno-associated viral vectors: implications for preclinical gene therapy trials. Gene Ther 21:913-20
Cronin, Therese; Vandenberghe, Luk H; Hantz, Péter et al. (2014) Efficient transduction and optogenetic stimulation of retinal bipolar cells by a synthetic adeno-associated virus capsid and promoter. EMBO Mol Med 6:1175-90
Zinn, Eric; Vandenberghe, Luk H (2014) Adeno-associated virus: fit to serve. Curr Opin Virol 8:90-7

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