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.
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.
|Cideciyan, Artur V; Sudharsan, Raghavi; Dufour, Valérie L et al. (2018) Mutation-independent rhodopsin gene therapy by knockdown and replacement with a single AAV vector. Proc Natl Acad Sci U S A 115:E8547-E8556|
|Sudharsan, Raghavi; Elliott, Michael H; Dolgova, Natalia et al. (2018) Photoreceptor Outer Segment Isolation from a Single Canine Retina for RPE Phagocytosis Assay. Adv Exp Med Biol 1074:593-601|
|Sudharsan, Raghavi; Beiting, Daniel P; Aguirre, Gustavo D et al. (2017) Involvement of Innate Immune System in Late Stages of Inherited Photoreceptor Degeneration. Sci Rep 7:17897|
|Beltran, William A; Cideciyan, Artur V; Boye, Shannon E et al. (2017) Optimization of Retinal Gene Therapy for X-Linked Retinitis Pigmentosa Due to RPGR Mutations. Mol Ther 25:1866-1880|
|Aguirre, Gustavo D (2017) Concepts and Strategies in Retinal Gene Therapy. Invest Ophthalmol Vis Sci 58:5399-5411|
|Sudharsan, Raghavi; Simone, Kristina M; Anderson, Nathan P et al. (2017) Acute and Protracted Cell Death in Light-Induced Retinal Degeneration in the Canine Model of Rhodopsin Autosomal Dominant Retinitis Pigmentosa. Invest Ophthalmol Vis Sci 58:270-281|
|Cideciyan, Artur V; Roman, Alejandro J; Jacobson, Samuel G et al. (2016) Developing an Outcome Measure With High Luminance for Optogenetics Treatment of Severe Retinal Degenerations and for Gene Therapy of Cone Diseases. Invest Ophthalmol Vis Sci 57:3211-21|
|Boyd, R F; Sledge, D G; Boye, S L et al. (2016) Photoreceptor-targeted gene delivery using intravitreally administered AAV vectors in dogs. Gene Ther 23:223-30|
|Iwabe, Simone; Ying, Gui-Shuang; Aguirre, Gustavo D et al. (2016) Assessment of visual function and retinal structure following acute light exposure in the light sensitive T4R rhodopsin mutant dog. Exp Eye Res 146:341-53|
|Charng, Jason; Cideciyan, Artur V; Jacobson, Samuel G et al. (2016) Variegated yet non-random rod and cone photoreceptor disease patterns in RPGR-ORF15-associated retinal degeneration. Hum Mol Genet 25:5444-5459|
Showing the most recent 10 out of 27 publications