# Investigating the role of NMD in Nonsense Mutation Biology and Therapeutic Strategies

> **NIH NIH F31** · CASE WESTERN RESERVE UNIVERSITY · 2022 · $46,752

## Abstract

There is a great need for treatments for diseases caused by nonsense mutations. In the context of Cystic
Fibrosis (CF), caused by mutations in the CFTR gene, patients with two nonsense alleles lack CFTR-specific
treatments. CF provides a useful context in which to study nonsense mutation biology as CF is a well
characterized genetic disease, has numerous model systems, and has dozens of nonsense mutations within
CFTR. Nonsense-mediated decay (NMD) is the cellular process that degrades transcripts containing
premature termination codons caused by nonsense mutations. NMD acts as a treatment barrier in nonsense
mutation conditions by preventing protein from being translated as few nonsense transcripts remain in the cell.
NMD, however, does not affect all nonsense transcripts equally. NMD efficiency has been suggested to vary by
tissue, cell type, and even by patient. Furthermore, nonsense mutations in specific locations within the
transcript escape NMD. This proposal aims to study the heterogeneity of NMD in CF nonsense mutations and
the pharmacological correction of CF nonsense mutations. Novel mouse models containing CF nonsense
mutations predicted to escape NMD will be developed. Using these NMD resistant models, NMD efficiency will
be measured and compared to existing CF models containing NMD susceptible nonsense mutations. Using
existing and new CF nonsense mouse models, pharmacological correction of nonsense mutations will be
studied. NMD inhibitors will be investigated, as well as readthrough agents (capable of triggering the
readthrough of premature stop codons), and CFTR modulators (which promote CFTR protein folding and
function) will be tested independently and in combination in mouse and human intestinal organoids and
ultimately in vivo in nonsense mutation mouse models. The best pharmacological combination may differ for
each genotype or by NMD phenotype. Studying the role of NMD in CF heterogeneity and CF nonsense
mutation correction may elucidate better therapeutic strategies and provide evidence for pursuing a precision
medicine approach in CF. The training plan outlined in this proposal will strongly support a successful transition
to a career in translational research for the trainee. The training plan includes activities relating to science
communication, clinical and translational research, preclinical in vivo animal techniques, and bioinformatics.

## Key facts

- **NIH application ID:** 10533441
- **Project number:** 1F31HL166193-01
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Margaret Michicich
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 1
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10533441

## Citation

> US National Institutes of Health, RePORTER application 10533441, Investigating the role of NMD in Nonsense Mutation Biology and Therapeutic Strategies (1F31HL166193-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10533441. Licensed CC0.

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