# Unveiling the molecular mechanisms in TPM3-related myopathy and therapies

> **NIH NIH K99** · BOSTON CHILDREN'S HOSPITAL · 2022 · $106,202

## Abstract

Project Summary
Autosomal dominant TPM3-related myopathy is primarily caused by missense mutations in the TPM3 gene
that lead to muscle atrophy and weakness, and substantially affect patient’s quality of life. So far, there is no
treatment for TPM3-related myopathy.
K99 mentored phase: Currently, the absence of representative animal model systems limits the emergence of
new pathophysiological findings in TPM3-related myopathy as well as potential therapeutics. To overcome this
gap, we have recently generated CRISPR-based Tpm3 mice that carry one of the most prevalent mutations
seen in patients. Our objectives are (1) to study the muscle pathology in the humanized mouse model of
TPM3-related myopathy, and (2) to dissect the transcriptional changes in slow and fast myonuclear
populations. Furthermore, we have characterized a tpm3-deficient zebrafish that show similar
pathophysiological features of myopathy and holds promise for the development of complementary
approaches that would be inconceivable with mammalian model systems. We also aim (3) to generate
CRISPR-based tpm3 zebrafish that carry the same most prevalent mutation seen in patients.
R00 independent phase: Zebrafish have become a powerful model to accelerate the discovery of potential
therapeutics. Our objective is (4) to develop a drug screening assay in tpm3 zebrafish. Allele-specific RNA
interference has also emerged as a powerful strategy for dominant inherited diseases such as TPM3-related
myopathy. Based on our preliminary data, TPM3 haploinsufficiency is not the likely underlying mechanism of
the myopathy. To complement our study in zebrafish, we aim (5) to screen for siRNAs that suppress the
mutant allele expression without reducing the wild-type allele in in vitro experiments and to test their efficacy in
vivo in our Tpm3 mouse.
My long-term goal is to become an independent investigator with a lab that combines the genetic and
molecular tools to study the neuromuscular diseases and develop therapeutic approaches. During the K99
mentored phase, I will gain additional skills in conceptual, technical and career development aspects which will
enable me to make a successful transition to an independent position with my own research group.
My short-term goals are (1) to acquire further skills in experimental procedures to study the muscle pathology
in mouse and zebrafish, (2) to gain expertise in large-scale data analysis, (3) to improve my knowledge in the
design of therapeutic strategies for neuromuscular disorders, (4) to obtain an independent tenure-track
assistant professor position, and (5) to successfully obtain R01 funding within 5 years of this proposal.

## Key facts

- **NIH application ID:** 10523631
- **Project number:** 1K99AR080197-01A1
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Matthias Lambert
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $106,202
- **Award type:** 1
- **Project period:** 2022-07-29 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10523631

## Citation

> US National Institutes of Health, RePORTER application 10523631, Unveiling the molecular mechanisms in TPM3-related myopathy and therapies (1K99AR080197-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10523631. Licensed CC0.

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