# Correcting genetic disorders using predictable CRISPR/Cas9-induced exon skipping

> **NIH NIH R21** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $223,750

## Abstract

Project Summary
Genetic disorders pose a substantial health burden on the U.S. population. While traditional
therapies for these disorders have focused on ameliorating the downstream phenotypic
consequences, a revolution in genome editing is beginning to treat these diseases at the
genetic level. One promising form of genetic therapy is called exon skipping. In exon skipping,
the cell is forced to bypass the gene region that contains the mutation, producing a smaller
version of the protein that restores function. The first clinical success in exon skipping disease
treatment has recently received FDA approval for treatment of Duchenne muscular dystrophy
(DMD), and several exon skipping strategies have shown pre-clinical and clinical promise.
We propose a systematic pilot study to measure the potential of this exon skipping technique to
correct disease genes throughout the genome. First, we establish a computational approach to
identify exons known to harbor disease-causing mutations where it is unlikely to impact gene
function if that exon is excluded. Next, we computationally predict whether these exons are
likely to be skipped using our highly specific experimental technique. Then, we will apply a
novel, high-throughput CRISPR/Cas9 genome editing assay to eliminate the splice site (to
ultimately skip the adjacent exon) that quantifies the impact on splicing at thousands of these
intron-exon boundaries.
After determining a set of candidate exons that can be skipped efficiently, we will measure the
impact of CRISPR/Cas9-mediated exon skipping on transcript structure and gene function for
dozens of human disease exons, using appropriate cellular and biochemical assays for each
gene. This exhaustive approach promises to chart a systematic path toward classifying disease
genes that would be most amenable for future pre-clinical evaluation of permanent therapeutic
exon skipping.

## Key facts

- **NIH application ID:** 9868320
- **Project number:** 5R21HG010391-02
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Christopher Cassa
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $223,750
- **Award type:** 5
- **Project period:** 2019-02-11 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9868320

## Citation

> US National Institutes of Health, RePORTER application 9868320, Correcting genetic disorders using predictable CRISPR/Cas9-induced exon skipping (5R21HG010391-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9868320. Licensed CC0.

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