Of the retinal degenerative diseases that affect 9 million Americans, retinitis pigmentosa (RP) is the most devastating. In RP and age-related macular degeneration (AMD), progressive atrophy of rod photoreceptors leads to secondary death of cone photoreceptors. Gene therapy is a potential means to strengthen or restore rod viability, thereby preventing secondary cone loss. However, the first human gene-therapy trial for RP found improved visual function but did not slow degeneration of photoreceptors. The goal of this gene therapy- oriented proposal is to determine whether therapy is achievable in the context of an already diseased retina. RP resulting from cGMP phosphodiesterase-6 (PDE6) deficiency is an ideal model for studying progressive cell- autonomous degeneration of rods and subsequent, non-cell-autonomous cone loss. During the previous funding period, we succeeded in restoring PDE6 activity and retinal function for more than 11 months in PDE6- deficient mice by using viral gene transfer methods before the onset of degeneration. We now propose, in Aim 1, to determine whether mouse rods and cones can be rescued within a clinically relevant time window - that is, after the onset of degeneration when patients are usually diagnosed. To do this, we generate a novel inducible genetic rescue system that allows us to conditionally reverse PDE6-deficiency and to control numerical, temporal and spatial aspects of phenotypic reversal. We will use this nonsurgical and robust gene therapy approach to determine if vision restoration/preservation is influenced by the timing of rod rescue (Aim 1a), the number of rods rescued (Aim 1a), and non-autonomous effects of mutant rods (Aim 1b). To complement the study of RP and its rescue in animal models, we have developed a non-invasive autofluorescence imaging technique in mice during the previous funding period. Because FDA is yet to accept imaging biomarkers as a primary outcome measure for treatment efficacy for retinal diseases, we will investigate whether non-invasive imaging can be a surrogate to assess disease progression in both mice and humans (Aim 2). Without novel disease predictors to replace conventional tests that are not deemed not sensitive enough, it is challenging to determine the appropriateness of a therapeutic approach, and/or to establish a baseline from which to assess efficacy (disease progression or stabilization). The novel non-invasive imaging biomarkers will enable us to inform RP patients their disease prognosis and treatment options. Furthermore, they will address the urgency to advise newly expectant parents who already have one child diagnosed with RP. Taken together, this proposal is certain to 1) define the factors limiting interventional therapy;2) validate a new tool kit for pharmacological control of photoreceptor-specific expression of any gene in the European Conditional Mouse Mutagenesis Program cohort;3) identify novel imaging biomarkers of disease progression essential for assessing efficacy in phase 2 and 3 clinical trials and 4) aid current and future basic mechanistic studies of photoreceptor degeneration in humans and animal models.
Retinal degenerations affect 6.5% of Americans older than 40 years of age. Nine million people in the U.S. suffer from diseases that cause degeneration of photoreceptors - the light-sensing cells in the eye. The hallmark of these blinding diseases is photoreceptor death. When first diagnosed, most of our patients have already lost the majority of photoreceptors that mediate nighttime vision (rods);this, in turn, endangers the photoreceptors that mediate daytime vision (cones). The goal of this gene therapy-oriented proposal is to determine whether therapy is achievable in photoreceptor degenerations by measuring the pattern of rod and cone damage over time in mice and humans.
|Nong, Eva; Lee, Winston; Merriam, Joanna E et al. (2014) Disease progression in autosomal dominant cone-rod dystrophy caused by a novel mutation (D100G) in the GUCA1A gene. Doc Ophthalmol 128:59-67|
|Wert, Katherine J; Skeie, Jessica M; Bassuk, Alexander G et al. (2014) Functional validation of a human CAPN5 exome variant by lentiviral transduction into mouse retina. Hum Mol Genet 23:2665-77|
|Tsang, Stephen H; Burke, Tomas; Oll, Maris et al. (2014) Whole exome sequencing identifies CRB1 defect in an unusual maculopathy phenotype. Ophthalmology 121:1773-82|
|Yang, Jin; Li, Yao; Erol, Deniz et al. (2014) Generation of induced pluripotent stem cells from conjunctiva. Graefes Arch Clin Exp Ophthalmol 252:423-31|
|Yang, Jin; Li, Yao; Chan, Lawrence et al. (2014) Validation of genome-wide association study (GWAS)-identified disease risk alleles with patient-specific stem cell lines. Hum Mol Genet 23:3445-55|
|Bassuk, Alexander G; Sujirakul, Tharikarn; Tsang, Stephen H et al. (2014) A novel RPGR mutation masquerading as Stargardt disease. Br J Ophthalmol 98:709-11|
|Li, Yao; Wu, Wen-Hsuan; Hsu, Chun-Wei et al. (2014) Gene therapy in patient-specific stem cell lines and a preclinical model of retinitis pigmentosa with membrane frizzled-related protein defects. Mol Ther 22:1688-97|
|Wert, Katherine J; Sancho-Pelluz, Javier; Tsang, Stephen H (2014) Mid-stage intervention achieves similar efficacy as conventional early-stage treatment using gene therapy in a pre-clinical model of retinitis pigmentosa. Hum Mol Genet 23:514-23|
|Greenberg, Jonathan P; Sherman, Jerome; Zweifel, Sandrine A et al. (2014) Spectral-domain optical coherence tomography staging and autofluorescence imaging in achromatopsia. JAMA Ophthalmol 132:437-45|
|Gelman, Rony; Kiss, Szilard; Tsang, Stephen H (2014) Multimodal imaging in a case of deferoxamine-induced maculopathy. Retin Cases Brief Rep 8:306-9|
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