# SCGE Disease Models Studies Supplement:  Repair of a CFTR Nonsense Mutation Using Adenine Base Editing

> **NIH NIH UH3** · UNIVERSITY OF IOWA · 2022 · $490,858

## Abstract

Abstract: CFTR nonsense mutations cause a severe cystic fibrosis (CF) phenotype, unresponsive to current
small molecule therapies. Correcting CFTR nonsense mutations in 5–15% of airway epithelia by installing a
single nucleotide A>G change using an adenine base editor (ABE) should restore CFTR mediated Cl−
secretion to healthy levels. We have optimized amphiphilic shuttle peptides for delivery of CRISPR associated
nuclease ribonucleoproteins (RNP) to mouse airways and ABE RNP to rhesus monkeys, achieving therapeutic
editing levels ≥5%. We propose to deliver ABE RNP to the airways of mice bearing the human CFTR R553X
nonsense mutation. In this model, mouse CFTR exon 12 was entirely replaced with human exon 12 sequence.
While substitution for wildtype human sequence has no negative consequences on mice, introduction of
human R553X mutation in the substituted exon 12 causes a CF phenotype (intestinal obstruction at weaning,
loss of CFTR function in airway epithelia and intestinal organoids). This is one of the only animal models of a
CFTR nonsense mutation with a disease phenotype. We previously demonstrated ex vivo that ABE RNP
delivered using shuttle peptides can efficiently revert the R553X mutation in human airway cells. Our
overarching goals are 1) to optimize ABE8e RNP editing, 2) to repair the R553X mutation in the airway
epithelia of mice with sufficient efficiency to restore CFTR function, and 3) to investigate the safety, toxicity,
and off-target effects of the editing approach while advancing towards clinical trials with this method.

## Key facts

- **NIH application ID:** 10619058
- **Project number:** 3UH3HL147366-05S1
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** PAUL B MCCRAY
- **Activity code:** UH3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $490,858
- **Award type:** 3
- **Project period:** 2018-09-07 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10619058

## Citation

> US National Institutes of Health, RePORTER application 10619058, SCGE Disease Models Studies Supplement:  Repair of a CFTR Nonsense Mutation Using Adenine Base Editing (3UH3HL147366-05S1). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10619058. Licensed CC0.

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