A multi-investigator, multi-center research plan is proposed to develop and test gene-based retinal therapy in animal models (mouse and dog) for translation to patients with autosomal dominant RP caused by mutations in the rhodopsin gene (RHO). RHO mutations constitute one of the most common molecularly-identified causes of human RP, and more than 100 of them account for >12 % of RP. The proposal has been divided into 4 aims that will:
(Aim#1) develop viral vectors, promoters, knockdown constructs and replacement cDNAs, and compare the efficacy of a RHO cDNA augmentation approach, to that of an allele-independent knockdown and replacement strategy in two mouse models;
(Aim #2) evaluate in a large animal model (dog) which of these strategies provides optimal rescue of rods, (Aim #3) develop outcome measures for clinical trials of gene therapy in RHO-ADRP patients, and (Aim #4) evaluate the optimal strategy and vector construct (based on results of Aims #1 and 2) in pre-clinical safety studies. Six coordinated modules (M) are described, each with a specific set of aims that contributes in a unique but complementary way to the translational studies. M1 (Vector Development) will provide AAVs carrying knockdown (siRNA, ribozymes) reagents, and resistant (hardened) RHO cDNAs. M2 (Small Animal-mouse- Therapy Studies) will test the 2 gene therapy approaches in two mouse models. M3 (Large Animal Experiemntal Support) will produce the dogs, and provide infrastructure resources for this work). M4 (Large anima I- dog - Therapy Studies) will test the 2 approaches in a naturally -occurring canine model of RHO-ADRP. M5 (Human RHO-ADRP) will identify retinal regions that can be targeted for focal retinal therapy in patients. M6 (Vector safety studies in Animals) will conduct GLP-based preclinical toxicology and biodistribution studies in small and large animals to test the safety of the optimal (""""""""lead"""""""") therapeutic vector as the essential first step ro FDA consideration of an IND for a future Phase I Clinical Trial. The research studies described in this proposal represent a continuation of a longstanding collaboration between the module scientists that already has brought retinal gene therapy for RPE65-LCA patients to a Phase I clinical trial.

Public Health Relevance

Past experience in successfully translating a gene therapy approach for LCA to human patients, and the available resources that this consortium of investigators brings, is a unique opportunity to now target RHO- ADRP. This is one of the most common forms of inherited retinal degeneration for which there is currently no specific treatment available.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Resource-Related Research Projects (R24)
Project #
5R24EY022012-03
Application #
8634788
Study Section
Special Emphasis Panel (ZEY1-VSN (10))
Program Officer
Agarwal, Neeraj
Project Start
2012-03-01
Project End
2017-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
3
Fiscal Year
2014
Total Cost
$1,342,268
Indirect Cost
$345,897
Name
University of Pennsylvania
Department
Other Clinical Sciences
Type
Schools of Veterinary Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Marsili, Stefania; Genini, Sem; Sudharsan, Raghavi et al. (2015) Exclusion of the unfolded protein response in light-induced retinal degeneration in the canine T4R RHO model of autosomal dominant retinitis pigmentosa. PLoS One 10:e0115723
Beltran, William A; Cideciyan, Artur V; Iwabe, Simone et al. (2015) Successful arrest of photoreceptor and vision loss expands the therapeutic window of retinal gene therapy to later stages of disease. Proc Natl Acad Sci U S A 112:E5844-53
Genini, Sem; Guziewicz, Karina E; Beltran, William A et al. (2014) Altered miRNA expression in canine retinas during normal development and in models of retinal degeneration. BMC Genomics 15:172

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