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.
| Xu, Christine L; Park, Karen Sophia; Tsang, Stephen H (2018) CRISPR/Cas9 genome surgery for retinal diseases. Drug Discov Today Technol 28:23-32 |
| Kroeger, Heike; Grimsey, Neil; Paxman, Ryan et al. (2018) The unfolded protein response regulator ATF6 promotes mesodermal differentiation. Sci Signal 11: |
| Jauregui, Ruben; Park, Karen Sophia; Duong, Jimmy K et al. (2018) Quantitative Comparison of Near-infrared Versus Short-wave Autofluorescence Imaging in Monitoring Progression of Retinitis Pigmentosa. Am J Ophthalmol 194:120-125 |
| Apatoff, Mary Ben L; Sengillo, Jesse D; White, Eugenia C et al. (2018) Autologous stem cell therapy for inherited and acquired retinal disease. Regen Med 13:89-96 |
| Jauregui, Ruben; Park, Karen Sophia; Tsang, Stephen H (2018) Two-year progression analysis of RPE65 autosomal dominant retinitis pigmentosa. Ophthalmic Genet 39:544-549 |
| Velez, Gabriel; Tang, Peter H; Cabral, Thiago et al. (2018) Personalized Proteomics for Precision Health: Identifying Biomarkers of Vitreoretinal Disease. Transl Vis Sci Technol 7:12 |
| Jauregui, Ruben; Park, Karen Sophia; Duong, Jimmy K et al. (2018) Quantitative progression of retinitis pigmentosa by optical coherence tomography angiography. Sci Rep 8:13130 |
| Liu, Katherine Y; Sengillo, Jesse D; Velez, Gabriel et al. (2018) Missense mutation in SLIT2 associated with congenital myopia, anisometropia, connective tissue abnormalities, and obesity. Orphanet J Rare Dis 13:138 |
| DiCarlo, James E; Mahajan, Vinit B; Tsang, Stephen H (2018) Gene therapy and genome surgery in the retina. J Clin Invest 128:2177-2188 |
| Cui, Xuan; Jauregui, Ruben; Park, Karen Sophia et al. (2018) Multimodal characterization of a novel mutation causing vitamin B6-responsive gyrate atrophy. Ophthalmic Genet 39:512-516 |
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