# Modulation of Jagged1/Pitpna in DMD as a means of therapy

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2022 · $385,506

## Abstract

PROJECT SUMMARY/ABSTRACT
Duchenne Muscular Dystrophy (DMD) is a degenerative muscle wasting disease caused by mutations in the
dystrophin gene. The absence of dystrophin protein at the muscle sarcolemma results in increased muscle
susceptibility to contraction-induced damage as well as dysregulation of secondary signaling pathways, many
of which remain poorly understood. Despite advances in treatment strategies under investigation aimed at
restoration of dystrophin expression including viral delivery of mini-dystrophin, read-through of translation stop
codons, and exon skipping to restore the reading frame, there is no cure for DMD, and the identification of
therapies that improve pathology independent of dystrophin would be of significant value to patients. In this
vain, genetic modifiers of DMD are emerging as potential therapeutic targets. Our lab recently identified
Jagged1 and Pitpna as genetic modifiers of DMD pathology in a Golden Retriever Muscular Dystrophy
(GRMD) dog colony in which two exceptional “escaper” dogs exhibited a drastically milder phenotype than
typical GRMD dogs despite being dystrophin-deficient. Normally, GRMD dogs show a severe phenotype
similar to human DMD including early progressive muscle degeneration, fibrosis, and premature death often
within the first 2 years of life due to cardiopulmonary failure. Gene expression analyses of the escaper dogs
compared to severely affected GRMD dogs and control animals revealed that Jagged1 overexpression (OE)
and decreased Pitpna expression were hallmarks of the mild phenotype, which including maintained
ambulation and normal lifespan. In subsequent genetic studies of dystrophin-deficient zebrafish, we
demonstrated that modulation of Jagged1 and Pitpna prevents manifestation of the dystrophic muscle
phenotype, increases long-term survival, and improves swim performance. In primary myoblasts derived from
normal and DMD patients, we also showed that Jagged1 overexpression and Pitpna inhibition impact
AKT/PTEN signaling and improve myoblast fusion. Given this positive data, we will now extend our research of
Jagged1 and Pitpna modulation into the well-characterized mdx5cv mouse model of DMD. We will also
investigate genetic and pharmacological inhibition of PDE10A, which we have shown to elicit decreased Pitpna
expression and improve dystrophic pathology in dystrophin-deficient zebrafish. The long-term goal in this
project is to assess and validate the therapeutic potential of the genetic modifiers Jagged1 and Pitpna to
ameliorate DMD pathology, and to identify a viable pharmacologic modulator to advance into clinical studies.
To accomplish this, we will implement experiments in accordance to the following three specific aims: 1)
Determine the effect of reduced Pitpna expression on dystrophic pathology in mdx5cv mice, 2) Characterize the
functional role of Jagged1 overexpression in mdx5cv mice, and 3) Assess the therapeutic potential of PDE10A
inhibition on dystrophic pathology in p...

## Key facts

- **NIH application ID:** 10447111
- **Project number:** 5R01AR064300-09
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** LOUIS M KUNKEL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $385,506
- **Award type:** 5
- **Project period:** 2014-04-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10447111

## Citation

> US National Institutes of Health, RePORTER application 10447111, Modulation of Jagged1/Pitpna in DMD as a means of therapy (5R01AR064300-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10447111. Licensed CC0.

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