# CRISPR-Cas9 based treatment of dominant retinal degeneration

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2022 · $374,300

## Abstract

Abstract
Inherited retinal degenerations are a genetically heterogeneous group of disorders characterized by death of
the light-sensing photoreceptor cells of the outer neural retina. For decades, physicians and scientists have
dreamed of preventing vision loss in patients affected with an inherited retinal disease via some form of gene
replacement therapy. Thus, it is not surprising that the recent clinical success of AAV-mediated gene
augmentation for the treatment of early stage RPE65-associated disease has been tremendously exciting,
providing a new level of confidence that this approach will also be useful for the treatment of other recessive
and X-linked disorders. However, AAV-mediated gene augmentation is not likely to be effective as a stand-
alone treatment for the large population of patients with dominantly inherited diseases that result from
mutation dependent formation of a toxic protein product (i.e. gain of function variants).
To treat dominant gain of function diseases, correction of the mutant allele or suppression of the abnormal
transcript will be required. Recent advances in the field of CRISPR-based genome editing have shown great
promise for such applications. For instance, in a recent study, we demonstrated how the subretinal injection of
a CRISPR/Cas9 construct could be used to disrupt the disease-causing Pro23His rhodopsin allele at the DNA
level in pig retina via nonhomologous end joining (NEHJ). Unfortunately, the efficiency of disease allele
deletion was significantly lower than that required to have a clinically significant effect. In response to this poor
efficiency (and the fact that off-target effects are a real concern with in vivo genome editing), we have decided
to focus this renewal application on very recently developed CRISPR-based approaches to suppress
transcription and cleave specific mRNAs rather than permanent DNA modification. These newly developed
approaches are significantly less likely to induce deleterious off-target genomic modifications than traditional
CRISPR-based strategies. Likewise, as these approaches do not require DNA cleavage and repair they have the
potential to be significantly more efficient, in turn making them more suitable for in vivo applications.
The CRISPR-based approaches outlined in this application will be tested in patient-specific iPSC-derived
retinal organoids in vitro and the Pro23His rhodopsin mutant pig in vivo. The studies in this proposal will
evaluate the feasibility of using this new dimension of CRISPR biology for the treatment of autosomal
dominant retinal diseases.

## Key facts

- **NIH application ID:** 10380840
- **Project number:** 5R01EY026008-06
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** EDWIN M STONE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $374,300
- **Award type:** 5
- **Project period:** 2016-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10380840

## Citation

> US National Institutes of Health, RePORTER application 10380840, CRISPR-Cas9 based treatment of dominant retinal degeneration (5R01EY026008-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10380840. Licensed CC0.

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