# Disease modeling and CRISPR/Cas9-mediated rescue of dominant Leber congenital amaurosis retinal phenotypes

> **NIH NIH F32** · OREGON HEALTH & SCIENCE UNIVERSITY · 2021 · $70,458

## Abstract

PROJECT SUMMARY/ABSTRACT
Leber congenital amaurosis (LCA) is a group of devastating early-onset retinal dystrophies affecting roughly
1/50,000 to 1/33,000 newborns. LCA-associated variants in the CRX gene result in a severe autosomal dominant
form of the disease, for which no effective treatments are currently available. Therefore, despite substantial
progress being made in the field, there is a critical need to uncover pathophysiology and establish reliable
treatment options for CRX-associated LCA. The overall goal of this proposal is to bring together two major
unsolved problems in vision research: (1) the ability to accurately recapitulate dominant LCA in a scalable in vitro
model system to study variant-specific disease mechanisms, and (2) the ability to efficiently and specifically
eliminate dominant disease alleles, leaving healthy alleles to restore photoreceptor cell function. In Aim 1,
variant-specific disease mechanisms responsible for the onset of LCA will be examined by generating a retinal
organoid model system from patient-derived induced pluripotent stem cells. These studies will establish a model
system for mechanistic characterization of LCA and will provide insight into alternative treatment strategies for
this disease. In Aim 2, mutant CRX alleles will be inactivated with CRISPR tools within the human retinal organoid
model to study rescue of disease phenotypes. Importantly, both mouse and human studies suggest that
haploinsufficiency is not responsible for disease manifestation in dominant CRX-associated LCA, and one copy
of wildtype CRX is enough to allow for mostly normal photoreceptor maturation and function. Completion of this
aim will provide the field with a proof-of-concept study for the development of patient-specific CRISPR-based
therapeutic strategies. Taken together, the proposed studies will contribute to our basic understanding of the
pathophysiological mechanisms underlying photoreceptor dysfunction in dominant CRX-associated LCA, and
will enable the development of targeted gene therapies to treat affected individuals.

## Key facts

- **NIH application ID:** 10140128
- **Project number:** 5F32EY031242-03
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Kathleen R Chirco
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $70,458
- **Award type:** 5
- **Project period:** 2020-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10140128

## Citation

> US National Institutes of Health, RePORTER application 10140128, Disease modeling and CRISPR/Cas9-mediated rescue of dominant Leber congenital amaurosis retinal phenotypes (5F32EY031242-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10140128. Licensed CC0.

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