# Therapeutic gene editing and multimodal imaging in juvenile macular degeneration

> **NIH NIH R24** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $2,189,617

## Abstract

Summary
FDA-approved gene therapy trials have treated autosomal-recessive (i.e., loss-of-function) disorders by
supplementation with the wild-type (WT) version of the mutant gene. For patients with autosomal-dominant (ad)
gain-of-function disorders, the best hope for a cure is genome surgery that repairs or removes the malfunctioning
genes at the root of the disease. Currently, that hope lies in CRISPR/Cas9-based gene editing {DiCarlo,
Mahajan & Tsang, J Clin Invest. 2018;128:2177}. The strength of the first-generation CRISPR-based therapy
(CRISPR1.0; Fig. 1)—its mutation-specificity—is also its greatest weakness. This is because the therapeutic
components for each mutation (both the guide RNA (gRNA) and the repair template) need to be custom-designed,
engineered, tested, and FDA-approved. This presents a considerable and costly challenge for the many ad
diseases caused by a slew of different mutations. For example, the blinding Best vitelliform macular dystrophy
(VMD) disorder is caused by any 1 of 250 different mutations in the rhodopsin (BEST1) gene. Treatment of all
patients would, therefore, require that 250 sets of CRISPR1.0 components be engineered, validated, and FDA-
approved.
To overcome this major limitation, we developed CRISPR2.0 (Fig.2), a mutation nonspecific strategy.
Unfortunately, CRISPR2.0 is not allele-specific and so eliminates both the mutant and WT alleles. As a result,
CRISPR2.0 requires gene supplementation, which leads to variable expression of the rescued gene and
sustainability concerns. We now propose to develop a third-generation CRISPR-based strategy, CRISPR3.0
(Fig. 2), that, like CRISPR2.0, is mutation nonspecific. However, CRISPR3.0 is allele-specific and therefore
ablates the mutant, disease-causing cis allele while leaving the WT allele intact to support normal function. We
hypothesize that CRISPR3.0 chromosome-specific genome surgery will produce a more sustained therapeutic
response compared to the CRISPR2.0 supplementation strategy.

## Key facts

- **NIH application ID:** 10155486
- **Project number:** 5R24EY028758-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Isabelle  AUDO
- **Activity code:** R24 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $2,189,617
- **Award type:** 5
- **Project period:** 2020-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10155486

## Citation

> US National Institutes of Health, RePORTER application 10155486, Therapeutic gene editing and multimodal imaging in juvenile macular degeneration (5R24EY028758-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10155486. Licensed CC0.

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