The longterm goals of the proposed research are to help define the genetic causality of inherited retinal degenerations (IRDs), improve our understanding of disease mechanisms, and develop effective gene and genetically directed therapies for these disorders. IRDs are important causes of blindness that are characterized by progressive dysfunction and death of the photoreceptor cells of the retina. Over 260 different types of IRDs have been identified across all age groups by clinical and genetic studies, but the specific genetic cause remains elusive in approximately one third of IRD patients. Further, the mechanisms by which identified mutations cause vision loss remain to be defined for many forms of IRD. Identifying the genetic cause of patients? IRD has become especially important with the recent success of clinical trials of gene therapy for RPE65-associated retinal degeneration. Further, studies in animal models have reported success of gene therapy for multiple additional genetic types of IRD, leading to clinical trials for several other genetic forms of IRD. There is thus an unprecedented opportunity to translate research progress into sight preserving treatment for patients with IRDs. The goal of the proposed research is to capitalize on this opportunity via a set of integrated Aims focused on identification of additional novel genetic causality of IRDs, including new disease genes and non-coding mutations, and development of gene and genetic therapies for one form of IRD.
In Aim 1, the genetic and functional studies needed to evaluate candidate disease genes identified through whole exome sequencing (WES) of families and cohorts of patients with IRDs will be performed. The applicant is part of the Joint Center for Mendelian Genomics at the Broad Institute, via which the WES for these studies is being performed. In addition to novel disease genes, data suggest that much of the missing genetic causality for IRDs is due to non- coding mutations and structural variants (SVs) in known and potentially novel IRD disease genes.
In Aim 2, whole genome sequencing (WGS) and transcriptome analyses will be used to search for novel non-coding genetic causality of IRDs in families with previously elusive genetic causes of disease. To build on the understanding gained by helping define the genetic causality of IRDs, the mechanisms by which mutations in the NMNAT1 gene cause retinal cell death and potential therapies for NMNAT1-associated disease will be studied in Aim 3. The NMNAT1 enzyme is required for nuclear NAD+ synthesis, and is widely expressed. Based on data obtained to date, it is hypothesized that by disrupting NAD+ homeostasis, mutations in NMNAT1 predispose cells to death via parthanatos, a cell death mechanism involved in other forms of neurodegeneration. It is further hypothesized that since retinal cells are highly metabolically active and sensitive to oxidative stress, they are more susceptible to parthanatos in the setting of NAD+ depletion than other cell types. These hypotheses will be tested, and the information applied to develop and test potential therapies for NMNAT1-associated disease.

Public Health Relevance

The goals of the proposed research are to investigate the genetic causes of inherited retinal degenerations (IRDs), and to develop gene and genetic therapies for these disorders. IRDs are important causes of vision loss, and the genetic basis of disease has been identified for only 2/3rds of patients afflicted with these disorders. Further, gene therapies for two genetic types of IRD have been shown to be beneficial in people, suggesting that gene and genetically directed therapies could be helpful for many forms of these diseases.

National Institute of Health (NIH)
National Eye Institute (NEI)
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Diseases and Pathophysiology of the Visual System Study Section (DPVS)
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Shen, Grace L
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Massachusetts Eye and Ear Infirmary
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