Thursday, November 21, 2024
11/21/2024
Project Summary/Abstract The long-term goals of the proposed research are to identify the genetic causes of inherited retinal degenerations (IRDs), define the mechanisms by which mutations in IRD disease genes lead to retinal degeneration, and to use this information to develop effective therapies to prevent vision loss from these blinding disorders. IRDs are important causes of vision loss that affect people across the age spectrum. While great progress has been made identifying the genetic causes of IRDs, approximately 1/3rd of patients have genetic causality that remains elusive. Further, the mechanisms by which mutations in specific IRD disease genes cause retinal degeneration remain to be defined for the majority of IRD disease genes. Identifying the genetic causes of IRDs and the mechanisms of disease pathogenesis has become especially important as genetic therapies such as gene augmentation therapy and neuroprotective therapies show great promise for the treatment of IRDs. But several challenges remain to be addressed to succeed with broad application of genetically informed therapies for IRDs. These include the need to define genetic causality for the 1/3rd of patients with elusive genetic causes of disease, and the need to more completely define the cellular mechanisms that connect mutations in a given gene with photoreceptor and RPE degeneration. The goal of Aim 1 is to address the first of these challenges. Evidence suggests that the majority of IRD disease genes have been identified, leading to the hypothesis that much of the missing genetic causality in the 1/3rd of IRD patients resides in the non-coding portions of the currently known IRD disease genes. It is challenging, however, to determine which of the 100s of rare deep intronic variants identified by whole genome sequencing (WGS) in IRD genes in patients with IRDs are pathogenic. In Aim 1 a novel high throughput splicing assay (HTSA) will be used to empirically test the functional effects of rare deep intronic variants identified in patients with IRDs and to prospectively characterize rare deep intronic variants in actionable IRD genes. The goal of Aim 2 is to address the second challenge by studying the mechanisms by which mutations in NMNAT1 cause severe early onset IRD. Despite being required for nuclear NAD+ synthesis in all cells, reduced NMNAT1 function causes retina-specific disease in most patients. Data from studies using a mouse model of NMNAT1- associated disease suggest that photoreceptor cells have the greatest demand for DNA repair of any cells in the human body and thus are the most vulnerable to reduced NMNAT1 function. To identify the source(s) of the DNA damage that underlie this high demand for DNA repair in photoreceptor cells the DNA modifications that accumulate and the DNA damage response pathways that are activated in mouse and human models of NMNAT1-associated disease will be studied in Aim 2. The results of these studies could inform development of additional therapies for NMNAT1-associated IRD, and potentially other forms of IRD as well.
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