Inherited retinal dystrophies (IRDs) are associated with a wide range of phenotypes affecting individuals from early childhood to late adulthood. Retinitis pigmentosa (RP), the most common IRD, is characterized by progressive retinal degeneration, often leading to complete loss of vision. Currently, 60 genes have been identified to harbor mutations that lead to RP. Mutations in the Retinitis pigmentosa 1 (RP1) gene are the third most common cause of RP. RP1 is a microtubule associated protein that localizes to the axoneme of photoreceptor outer segments, and mutations in RP1 cause both autosomal dominant and autosomal recessive RP via a dominant negative mechanism. These properties make RP1 an attractive target for gene therapy. While adeno-associated virus (AAV)-mediated gene delivery is well-studied, and has been shown to be a robust and effective gene therapy method, RP1 is too large to be packaged into the AAV capsid, necessitating the identification of an alternative strategy. Using RNA-Seq, we have comprehensively characterized the retinal transcriptomes from both mouse and human, identifying a conserved minor isoform of RP1 (nRP1). nRP1 contains an open reading frame that is roughly half the length of the major RP1 isoform, making it amenable to packaging into AAV. Importantly, it maintains the doublecortin domains vital for microtubule binding. Our preliminary studies have shown that nRP1 localizes to microtubules in vitro and to the axoneme in vivo, suggesting it is functionally similar to the canonical RP1. We hypothesize that nRP1 is functionally homologous to canonical RP1, and it can be used as an alternative gene therapy strategy to treat RP1-associated RP.
In Aim 1, we will comprehensively characterize the function of nRP1 in both in vitro and in vivo systems. This will provide one of the first functional characterizations of a minor isoform of any IRD gene.
In Aim 2, we will continue our complete characterization of nRP1 by generating a transgenic mouse model. This will serve two purposes: 1) to study endogenous expression of nRP1, and 2) to be used to determine the therapeutic potential of nRP1 in the next Aim.
In Aim 3, we will test the therapeutic potential of nRP1 by crossing our transgenic line developed in Aim 2 with a dominant and recessive Rp1-mutant model. By introducing nRP1 using a transgenic mouse model, rather than using AAV, we will be able to better determine functional and morphological rescue, as the whole eye will be expressing nRP1, rather than isolated expression at the site of an AAV injection. This proposal is an important first step in determining the function and therapeutic potential of nRP1. Further, this work will serve as a template for other IRD genes that are too large to be packaged into AAV.

Public Health Relevance

Gene therapy for inherited retinal dystrophies has proven to be an effective and safe treatment. The goal of the proposed research is to investigate the use of a novel, small RP1 isoform as a replacement for the canonical, AAV-incompatible isoform, thus creating an alternative gene therapy strategy for RP1-associate retinitis pigmentosa, a currently untreatable disease.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Diseases and Pathophysiology of the Visual System Study Section (DPVS)
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Neuhold, Lisa
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State University of New York at Buffalo
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United States
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