# Dystrophin and Heart Disease

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2020 · $383,310

## Abstract

Abstract
Significant health relevance of this application is evident in our mechanistic dissection of the role of the
cytoskeletal protein dystrophin in heart health and disease. Numerous inherited and acquired cardiac diseases
are caused by deficits in dystrophin, including, notably, Duchenne muscular dystrophy (DMD), in which there is
the complete loss of the dystrophin protein. Dystrophin is a 427 kDa cytoskeletal protein and is a vital link
between the cytoskeleton, the muscle membrane and the extracellular matrix. Heart disease accounts for a
significant mortality in DMD, for which there is no cure or long-term effective treatment. Recent advances in
genetic technologies have fueled enthusiasm for gene-based therapeutic restitution of truncated dystrophins as
a treatment for DMD. For DMD patients, several exon skipping clinical trial studies are ongoing and proof-of-
concept somatic cell gene editing studies provide evidence of effectiveness in animal models. To date, none of
these efforts have successfully translated to clinical efficacy in DMD patients. We posit reduced in vivo stability
of internally truncated dystrophins is a significant barrier to ultimate clinical efficacy. We provide preliminary
evidence that truncated dystrophins can be highly unstable in vivo, with markedly faster turnover rates than full
length dystrophin. Reduced stability of a truncated dystrophin is expected to have significant implications for
long-term clinical success by negatively impacting duration of therapeutic action in vivo. Further, the therapeutic
expression threshold to confer significant cardio-protection with truncated dystrophin molecules is not known
and truncated dystrophin proteins can confer only partial physiological restitution in dystrophin-deficient hearts
in vivo. We have established a proof-of-concept approach to directly determine the stability and physiological
expression threshold for truncated dystrophins in the heart in vivo. Guiding hypothesis: Clinically-designed gene
therapy, gene-edited or exon skipped truncated dystrophin molecules will have significantly shorter half-lives in
the heart in vivo, compared to intact full length dystrophin, compromising duration of action effects. The Specific
Aims are to establish the in vivo stability/half-life of clinically relevant truncated dystrophins in the dystrophic
heart. This knowledge is essential for the success of gene-based clinical trials for DMD. These studies will have
a lasting impact on the field by illuminating the key dystrophin structure-function benchmarks required for long-
term effectiveness of current and future gene-based therapies for DMD patients.

## Key facts

- **NIH application ID:** 9931293
- **Project number:** 5R01HL138490-04
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** JOSEPH Mark METZGER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $383,310
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9931293

## Citation

> US National Institutes of Health, RePORTER application 9931293, Dystrophin and Heart Disease (5R01HL138490-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9931293. Licensed CC0.

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