We propose to continue using AAV vectors as a gene delivery vehicle to explore ways to rescue, restore or delay loss of retinal structure and function in animal models of retinal dystrophy (RD). We will focus primarily on seven recessive mouse models for human retinal degenerations representing a broad range of human RDs affecting rods, cones or the RPE. Four will be carried out primarily in-house while three are continuing collaborations with other investigators. Our overall hypothesis is that gene-based therapies will be clinically useful for a wide variety of RDs and that the safest and most effective AAV vectors will be those that incorporate serotypes and promoters with the ability to target passenger gene expression preferentially to the affected retinal cell type. We have chosen to focus on genetically and phenotypically well-characterized RD rodent models encompassing as wide a variety of disease classes and target cells as possible in order to fully assess the generality of our hypotheses. These include gene replacement therapy for the rd10 mouse, a rod PDEbeta recessive RP model, the ABCA4 knock out mouse, a model for recessive Stargardt's disease, the RS-1 knock out mouse, a model for X-linked Retinoschisis, the rd12 mouse, a model for RPE65 LCA, the LRAT knock out mouse, a model for recessive childhood RP, the Cpfl3 mouse, a model for Achromotopsia 2 (recessive GANT2 mutation), and the Cpfl1 mouse, a model for cone PDE6c recessive cone dystrophy. In addition we will test the efficacy of X-linked Inhibitor of Apoptosis (XIAP) in many of these mouse models by first crossing them into a transgenic line containing constitutively expressed XIAP in photoreceptors and RPE cells. For those models that respond, AAV-XIAP therapy will be tested. This proposal will also support vector production for more general retinal survival strategies through collaborations: AAV-XIAP, AAV-CNTF and/or AAV-CNTFalpha vectors will be employed in the rds mouse, the Cancer Associated Retinopathy (CAR) rat and in the P23H transgenic rat. In most cases we have already obtained initial proof-of-principle therapeutic results while for a few such experiments are just beginning. Our goals will be to characterize the magnitude and duration of therapy, to determine the age window within which therapy is effective and to define any retino-toxic effects of therapy, particularly over longer post-treatment periods. Ultimately we view this broad but systematic approach to validating the effectiveness and safety of AAV-vectored RD gene therapies as a necessary part of the initial preclinical safety/efficacy data required before translation to clinical trials on each analogous human disease could begin.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
Project #
Application #
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Neuhold, Lisa
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Florida
Schools of Medicine
United States
Zip Code
Ku, Cristy A; Chiodo, Vince A; Boye, Sanford L et al. (2015) Viral-mediated vision rescue of a novel AIPL1 cone-rod dystrophy model. Hum Mol Genet 24:670-84
Dai, Xufeng; Han, Juanjuan; Qi, Yan et al. (2014) AAV-mediated lysophosphatidylcholine acyltransferase 1 (Lpcat1) gene replacement therapy rescues retinal degeneration in rd11 mice. Invest Ophthalmol Vis Sci 55:1724-34
Zhu, Yongling; Xu, Jian; Hauswirth, William W et al. (2014) Genetically targeted binary labeling of retinal neurons. J Neurosci 34:7845-61
Boye, Sanford L; Peshenko, Igor V; Huang, Wei Chieh et al. (2013) AAV-mediated gene therapy in the guanylate cyclase (RetGC1/RetGC2) double knockout mouse model of Leber congenital amaurosis. Hum Gene Ther 24:189-202
Komáromy, András M; Rowlan, Jessica S; Corr, Amanda T Parton et al. (2013) Transient photoreceptor deconstruction by CNTF enhances rAAV-mediated cone functional rescue in late stage CNGB3-achromatopsia. Mol Ther 21:1131-41
Deng, Wen-Tao; Dinculescu, Astra; Li, Qiuhong et al. (2012) Tyrosine-mutant AAV8 delivery of human MERTK provides long-term retinal preservation in RCS rats. Invest Ophthalmol Vis Sci 53:1895-904
Verma, Amrisha; Shan, Zhiying; Lei, Bo et al. (2012) ACE2 and Ang-(1-7) confer protection against development of diabetic retinopathy. Mol Ther 20:28-36
Dinculescu, Astra; Estreicher, Jackie; Zenteno, Juan C et al. (2012) Gene therapy for retinitis pigmentosa caused by MFRP mutations: human phenotype and preliminary proof of concept. Hum Gene Ther 23:367-76
Light, Adam C; Zhu, Yongling; Shi, Jun et al. (2012) Organizational motifs for ground squirrel cone bipolar cells. J Comp Neurol 520:2864-87
Gorbatyuk, Marina S; Gorbatyuk, Oleg S; LaVail, Matthew M et al. (2012) Functional rescue of P23H rhodopsin photoreceptors by gene delivery. Adv Exp Med Biol 723:191-7

Showing the most recent 10 out of 91 publications