# miR-145 target site blockade is a selective strategy to enhance CFTR restoration and readthrough

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2021 · $371,250

## Abstract

PROJECT SUMMARY
 Cystic fibrosis (CF), a life-limiting autosomal recessive lung disease that affects 1 in 3500
children, is caused by mutations in the Cystic Fibrosis Transmembane conductance Regulator
(CFTR) gene. Recently FDA-approved CFTR modulators partially improve lung function for the
most prevalent mutation (F508del), but other common genotypes, such as premature
termination codon (PTC) nonsense mutations, lack an effective intervention. Even in F508del
patients, 25% are low responders to the latest triple combination modulator cocktail.
 We discovered that a small non-coding microRNA called miR-145 regulates CFTR gene
expression and blocks efficacy of CFTR modulators. Our previous data show that complete
miR-145 antagonism improves F508del therapy. This project will pursue a more precise strategy
that utilizes an antisense oligonucleotide (ASO) to sterically impede only miR-145 binding to
CFTR without interrupting other pathways.
 We hypothesize that ASO-directed miR-145 target site blockade improves CFTR correction.
We propose 3 Aims:
 Specific Aim #1: Enhance F508del CFTR correction selectively through ASO blockade
of the miR-145 binding site.
Specific Aim #2: Bolster CFTR correction through miR-145 manipulation in low
responders.
Specific Aim #3: Employ miRNA inhibition to augment readthrough efficacy in PTC
mutations.
 Together, these Aims investigate miR-145 inhibition as a novel strategy to improve next-
generation CFTR correction. Aim 1 tests the efficacy and selectivity of ASO target site blockade
to enhance CFTR modulator response in F508del CF airway epithelial cells and relevant animal
models. Aim 2 uses patient-derived nasal samples from low responders to FDA-approved CFTR
modulators to test whether miR-145 inhibition boosts individual benefit. Aim 3 investigates using
miR-145 inhibition to increase the CFTR substrate available for PTC readthrough in mutations
that currently lack an effective therapy. These experiments will examine a novel, highly selective
strategy to advance CFTR-directed therapeutics, broadly applicable across CFTR intervention
and patient genotype.

## Key facts

- **NIH application ID:** 10298470
- **Project number:** 1R01HL155119-01A1
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** William Thomas Harris
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $371,250
- **Award type:** 1
- **Project period:** 2021-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10298470

## Citation

> US National Institutes of Health, RePORTER application 10298470, miR-145 target site blockade is a selective strategy to enhance CFTR restoration and readthrough (1R01HL155119-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10298470. Licensed CC0.

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