The long-term goals of the proposed research are to enhance understanding of the molecular bases of inherited retinal degenerations (IRDs) so that improved therapies can be developed for these blinding disorders. In the past funding cycle, significant progress has been made toward these goals, and the team is poised to make further progress via the proposed research. IRDs are important causes of blindness that are characterized by progressive dysfunction and death of rod and cone photoreceptor cells. Over 200 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 half 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 Leber congenital amaurosis (LCA). 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 provide sight preserving and/or restoring treatment to patients with IRDs. The genetic diversity of IRDs presents a challenge to developing therapies for these disorders. The goal of the proposed research is to apply a systematic approach from disease gene discovery through studies of disease pathogenesis to development of gene therapies to meet this challenge and translate progress into treatments for these disorders.
In Aim 1, a combination of optimized whole exome sequencing and copy number variant analysis will be used to identify additional IRD disease genes. This addresses both the need to identify novel disease genes, and the challenges associated with using exome sequencing for disease gene discovery.
In Aim 2, the function of the NMNAT1 and TTC21B genes in the retina, and how mutations in these genes cause retinal degeneration will be investigated. In the past funding cycle, mutations in NMNAT1 and TTC21B were identified as causes LCA and syndromic IRD, respectively. With regard to NMNAT1, these findings imply that NAD+- dependent signaling in the nucleus plays an important role in retinal biology. With regard to TTC21B, this highlights the importance of retrograde intraflagellar transport (IFT) in multiple types of cilia, including photoreceptor sensory cilia.
In Aim 3, the hypothesis that gene augmentation therapy can provide therapeutic benefit for RP1 disease will be tested. This is a logical extension of prior work, in which the function of the RP1 protein was investigated, and it was determined that mutations in RP1 cause dominant disease via a dominant- negative mechanism, suggesting that gene augmentation therapy has the potential to be beneficial for both dominant and recessive forms of RP1 disease. Viewed together, the Aims of the proposed research provide a logical pathway to facilitate translation of research findings regarding the causes of IRDs into therapies.

Public Health Relevance

The goals of the proposed research are to investigate the genetic causes of inherited retinal degenerations (IRDs), and work towards developing gene therapies for these disorders. IRDs are important causes of vision loss, and the genetic basis of disease has been identified for only half of patients afflicted with these disorders. Further, gene therapy for one genetic sub-type of IRD has been shown to be successful in people, suggesting that gene therapy could be beneficial for multiple genetic forms of these disorders.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (DPVS)
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Shen, Grace L
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Massachusetts Eye and Ear Infirmary
United States
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