Mechanism of photoreceptor cell degeneration in animal models of retinal diseases

University Of Houston, Houston TX

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Abstract

PROJECT SUMMARY The gene encoding peripherin 2 (PRPH2), is mutated in 3-5% of inherited retinal degeneration (IRD) cases. PRPH2 variants lead to a spectrum of retinal diseases, including retinitis pigmentosa (RP) and various forms of macular and pattern dystrophy (PD). These diseases often entail secondary impairments in adjacent tissues like the RPE and retinal/choroidal vasculature. Despite considerable scientific advancement, the lack of clinically viable therapeutic options for PRPH2 retinal diseases persists due to several factors including the diverse roles of PRPH2/ROM1 (retinal outer segment membrane protein 1, a core binding partner of PRPH2) in rods versus cones, limited genotype/phenotype correlations, extensive variability in disease phenotypes within and between families, the role of secondary sequalae in disease progression, and the necessity for precise PRPH2 dosage to offset the effects of its haploinsufficiency. PRPH2 plays a crucial role in the formation, maintenance, and renewal of the outer segment (OS). In its absence rod OSs are not formed. On the other hand, cones form extended membranous structures that lack evaginations of the lamella but retain function, highlighting the different roles for PRPH2 in rods and cones. We aim to elucidate the precise role of PRPH2 and ROM1 complexes in OS rim, incisure, and disc/lamella formation, and to expand our knowledge of the PRPH2 interactome with the goal of potentially influencing severity of disease phenotypes. Gaining a thorough grasp of the mechanisms associated with PRPH2 diseases is crucial for designing effective therapies. The mechanisms underlying photoreceptor disc morphogenesis are not well understood and are of longstanding interest. To bridge the gaps in our knowledge, we established mouse models and various therapeutic platforms, enabling us to evaluate disease mechanisms and test therapeutic strategies for PRPH2 diseases. Our multidisciplinary team is comprised of leaders in photoreceptor cell and molecular biology, advanced imaging technologies, structural biology, and non-viral therapeutic formulations and will employ cutting-edge experiments to achieve the following objectives: 1) Investigate the role of PRPH2 complexes in forming the highly curved, hairpin-shaped disc rim structures crucial for OS formation. 2) Explore ROM1’s influence on disc rim morphogenesis, particularly in timely closure of the newly synthesized discs and incisure formation. 3) Identify interacting partners contributing to the diverse disease phenotypes associated with PRPH2 variants. 4) Investigate mechanisms underlying variability among patients with identical PRPH2 variants. 5) Develop therapeutic platforms to mitigate severe PRPH2- associated phenotypes. Understanding these mechanisms is crucial for advancing our knowledge of OS morphogenesis and the diversity of PRPH2-associated disease phenotypes.