# Translational Research for Retinal Degeneration Therapies

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $774,244

## Abstract

A multi-investigator, multi-center plan is proposed to develop gene-based retinal therapies for LCA-
ciliopathies using the dog NPHP5 model. A subgroup of these human ciliopathies show early onset and
profound congenital retinal and visual malfunction that results from abnormally developed photoreceptors
(PR) that subsequently degenerate. The proposal builds on success achieved in the current grant period in
moving RPGR-XLRP to a clinical trial, and recent studies in the NPHP5 model showing that a scAAV2/8-
based viral vector, together with the human GRK1 promoter and human full-length NPHP5 cDNA, rescues
ERG rod and cone function, and vision, for at least 1 year, but that PRs continue to degenerate, albeit at a
much slower rate. This vector now serves as the benchmark test vector to assess treatment paradigms to
optimize PR targeting, infectivity and therapeutic transgene expression that will result in permanent disease
correction. The proposal will evaluate gene therapy in dogs having this aggressive and severe LCA-
ciliopathy, and is divided into three aims that will: 1- establish the benchmark dose and disease stage
treatment efficacy of the test vector; 2- select the lead vector pseudotype and promoter with optimized
transduction efficiency, and efficacy in targeting different PR disease stages; 3- facilitate translational studies
by defining the natural history of the disease in dogs and patients, the effect of treatment in dogs, and
determining the degree of PR/retinal disease still amenable to treatment. While the test platform is the
NPHP5-LCA dog model, the therapeutic questions addressed apply broadly to other LCA-ciliopathies. Four
coordinated groups [a.k.a. modules (M)], are described that take advantage of the special expertise of each
group to create a complementary and focused approach to the proposed translational studies. M1 (Large
Animal Experimental) will produce the dog models, and provide infrastructure resources for the work; M2
(Large Animal Therapy) will carry out therapy studies and develop measures for outcome assessment; M3
(Non-invasive Patient and Dog Studies) will establish functional and structural disease features in the
patients and model, and evaluate success of therapies in dogs using non-invasive outcome measures that
correlate with ex vivo morphologic studies; M4 (Molecular Therapeutic Development) will provide therapeutic
vectors. The research studies described in this proposal represents a continuation of a longstanding
collaboration between the module scientists that already has brought retinal gene therapy for the treatment
of patients with RPE65-LCA (Phase I clinical trial), and CNGB3-achromatopsia and RPGR-XLRP (both in
final preparations for clinical trials). The University of Pennsylvania leads this collaboration with the
University of Florida.

## Key facts

- **NIH application ID:** 10004613
- **Project number:** 5R01EY017549-14
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** GUSTAVO David AGUIRRE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $774,244
- **Award type:** 5
- **Project period:** 2007-09-30 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10004613

## Citation

> US National Institutes of Health, RePORTER application 10004613, Translational Research for Retinal Degeneration Therapies (5R01EY017549-14). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10004613. Licensed CC0.

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