# Oligotherapeutics to enhance CFTR correction

> **NIH NIH R03** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $74,250

## Abstract

PROJECT SUMMARY
 Cystic Fibrosis (CF) is a fatal lung disease that affects 1 in 3500 children. F508del CFTR,
the most common mutation present in 90% of CF patients, has proven difficult to treat. The two
FDA approved drugs, Orkambi® (lumacaftor and ivacaftor) and Symdeko® (tezacaftor and
ivacaftor), only improve lung function by 2-4%. Improving F508del CFTR remains a critical
unmet need in CF therapeutics.
 One barrier to F508del CFTR correction is increased expression of the genetic modifier
TGF-β in CF lung and airway epithelia. TGF-β suppresses CFTR function and nullifies the
benefit of Orkambi® and Symdeko®. Our laboratory has discovered that the microRNA miR-145
mediates TGF-β inhibition of CFTR correction. TGF-β increases miR-145 which directly binds to
the 3'-untranslated region (3'-UTR) to degrade CFTR transcripts and diminish protein
expression. Loss of CFTR substrate eliminates therapeutic response. miR-145 antagonism
overcomes this barrier to improve Orkambi® benefit.
 The project pursues a novel approach to augment F508del therapeutics. We will utilize an
antisense oligonucleotide (ASO) to block miR-145 binding to CFTR. We hypothesize that ASO-
directed miR-145 target site blockade improves F508del CFTR correction.
Specific Aim #1: To selectively augment F508del CFTR correction through antisense
oligonucleotide blockade of the miR-145 binding site.
Specific Aim #2: To test in vivo delivery, safety, and efficacy of antisense oligonucleotide
miRNA target specific blockade in humanized CFTR mice.
 These Aims will provide the necessary “next steps” in oligotherapeutic development. Aim 1
provides the in vitro mechanism, dosing, and efficacy data to establish the rationale for
oligonucleotide targeting of the miRNA binding site to improve F508del CFTR correction. Aim 2
utilizes the recently developed full-length humanized CFTR mouse to establish delivery
feasibility, safety profile, and therapeutic response in vivo.

## Key facts

- **NIH application ID:** 10000198
- **Project number:** 5R03HL148467-02
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** William Thomas Harris
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $74,250
- **Award type:** 5
- **Project period:** 2019-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10000198

## Citation

> US National Institutes of Health, RePORTER application 10000198, Oligotherapeutics to enhance CFTR correction (5R03HL148467-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10000198. Licensed CC0.

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