# Mechanistic analysis and allellic genome editing of iPSC-derived dominant LCA model

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $391,638

## Abstract

PROJECT SUMMARY
 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. 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. 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, we will develop and characterize iPSC-based disease models from two different dominant
variants of CRX. We will validate disease phenotypes using retinal organoids. In Aim 2, 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. In Aim 3, mutant CRX alleles will be inactivated with CRISPR
tools within the human retinal organoid model to study rescue of disease phenotypes. 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:** 10319983
- **Project number:** 5R01EY032197-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Deepak Ashok Lamba
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $391,638
- **Award type:** 5
- **Project period:** 2021-01-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10319983

## Citation

> US National Institutes of Health, RePORTER application 10319983, Mechanistic analysis and allellic genome editing of iPSC-derived dominant LCA model (5R01EY032197-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10319983. Licensed CC0.

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