# Molecular and therapeutic correction of XMEA using novel zebrafish and mouse models

> **NIH TR R03** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2026 · $149,000

## Abstract

PROJECT SUMMARY/ABSTRACT
The objective of this proposal is to define the molecular mechanisms and identify new therapeutic strategies for
of an understudied class of myopathies, specifically X-linked myopathy with excessive autophagy (XMEA).
XMEA is characterized by elevated levels of autophagy due to disruptions in the autolysosome function. One
MEA of interest is X-linked myopathy with excessive autophagy (XMEA), a rare autophagic vacuolar myopathy
that characterized by progressive proximal muscle weakness, high levels of serum creatine kinase and
accumulation of autophagic vacuoles. XMEA is caused by pathogenic mutations in the VMA21 gene in which N-
terminal loss-of-function variants result in early death by 10 years and milder pathogenic VMA21 splicing variants
result in a slower disease progression. Patients with VMA21 pathogenic mutations have a defective autophagy
and an impaired ability to form the autophagosomes. VMA21 is a subunit of the V-ATPase protein pump and its
disruption results in a failure to properly acidify the autolysosome resulting in the formation of vacuolar inclusions
in XMEA. No extensive biomarker studies have been performed in the XMEA population resulting in a dearth of
knowledge and the lack of suitable XMEA models is a significant barrier towards any effective treatment.
We have generated a Vma21 knock-in (Vma21 KI) mouse model based on an RNA-splice mutation identified in
a set of XMEA patients observed at our Children’s of Alabama muscular dystrophy clinic. Vma21 KI mice have
a progressive muscle weakness, impaired muscle function, and have vacuolar inclusions that form as they age,
which phenocopies the XMEA patient symptoms. In parallel, we generated vma21 mutant zebrafish that have a
severe loss-of-function (LoF) pathology resulting in muscle paralysis, vacuolar inclusion bodies, and early
lethality by 10 days post fertilization (dpf). An autophagy drug library screen of our vma21 mutant zebrafish
identified edaravone, an FDA-ap

## Key facts

- **NIH application ID:** 11265724
- **Project number:** 1R03TR005967-01
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** MATTHEW Scott ALEXANDER; Michael Alonzo Lopez
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** TR
- **Fiscal year:** 2026
- **Award amount:** $149,000
- **Award type:** 1
- **Project period:** 2026-02-01T00:00:00 → 2027-01-31T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11265724

## Citation

> US National Institutes of Health, RePORTER application 11265724, Molecular and therapeutic correction of XMEA using novel zebrafish and mouse models (1R03TR005967-01). Retrieved via AI Analytics 2026-06-24 from https://api.ai-analytics.org/grant/nih/11265724. Licensed CC0.

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