# CRISPR/Cas9-Mediated Correction of Abca4 Mutations in a Stargardt Mouse Model

> **NIH NIH F30** · CASE WESTERN RESERVE UNIVERSITY · 2021 · $51,036

## Abstract

PROJECT SUMMARY
Stargardt disease (STGD1) is the most common form of inherited juvenile macular degeneration, leading to
progressive loss of central vision. STGD1 is caused by autosomal recessive mutations in the ATP Binding
Cassette Subfamily A Member 4 (ABCA4) gene, which encodes a membrane transporter, ABCA4, that facilitates
the removal of all-trans-retinals (atRALs) from photoreceptor outer segment disc membranes as part of the visual
cycle. Mutations in ABCA4 result in the accumulation of toxic atRALs and atRAL condensation products (A2E)
and the subsequent degeneration of retinal pigment epithelial cells and photoreceptors. Despite its high
prevalence, STGD1 has no treatment at present. While gene replacement therapy using Adeno-Associated Virus
(AAV) has emerged as a promising therapy for inherited retinal diseases, the 4.7 kb gene capacity of the AAV
vector has hindered treatment of mutations in larger genes such as ABCA4. However, the recent advent of
CRISPR/Cas9 technology has expanded the application potential of AAV for treating genetic diseases. The
CRISPR/Cas9 technology is an efficient genome editing technology, which can promote genomic modification
at specific sites. Several studies have successfully demonstrated the modification of disease-causing mutations
and rescue of the pathological phenotype in animal models by delivering CRISPR/Cas9 via AAV. These
promising results raise the prospect of using AAV and CRISPR/Cas9 to target ABCA4 mutations in the
photoreceptors of STGD1 patients. As proof-of-principle, I propose to demonstrate in vivo correction of ABCA4
mutations in the photoreceptors of an STGD1 mouse model using CRISPR/Cas9 technology. The STGD1 mouse
model carries two point mutations found in STGD1 patients and displays the corresponding phenotype. In Aim
1, I will validate the gene-editing efficacy of the CRISPR/Cas9 system in an explant culture derived from STGD1
mice. In Aim 2, I will package the validated CRISPR/Cas9 system into AAV vectors and deliver them by subretinal
injection in STGD1 mice. In Aim 3, I will assess the correction of STGD1 mutations and phenotype in mice
following the subretinal delivery. I envision that this proof-of-concept study will explore the efficacy of
CRISPR/Cas9 technology as a new therapeutic approach for STGD1 and lay a solid foundation for the
development of AAV and CRISPR/Cas9 combined treatment against any genetic ocular disease driven by a
known pathogenic mutation.

## Key facts

- **NIH application ID:** 10085647
- **Project number:** 5F30EY029136-03
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Susie Suh
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $51,036
- **Award type:** 5
- **Project period:** 2019-01-15 → 2022-01-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10085647

## Citation

> US National Institutes of Health, RePORTER application 10085647, CRISPR/Cas9-Mediated Correction of Abca4 Mutations in a Stargardt Mouse Model (5F30EY029136-03). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10085647. Licensed CC0.

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