# Using functional homology of RP1 isoforms to guide alternative therapeutic strategies

> **NIH NIH R01** · STATE UNIVERSITY OF NEW YORK AT BUFFALO · 2020 · $326,391

## Abstract

Abstract
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.

## Key facts

- **NIH application ID:** 9884767
- **Project number:** 5R01EY028553-03
- **Recipient organization:** STATE UNIVERSITY OF NEW YORK AT BUFFALO
- **Principal Investigator:** Michael Farkas
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $326,391
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9884767

## Citation

> US National Institutes of Health, RePORTER application 9884767, Using functional homology of RP1 isoforms to guide alternative therapeutic strategies (5R01EY028553-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9884767. Licensed CC0.

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