# Targeted Therapy for Pompe Disease

> **NIH NIH R01** · DUKE UNIVERSITY · 2020 · $348,356

## Abstract

7. PROJECT SUMMARY/ABSTRACT
 Pompe disease is a fatal neuromuscular disorder that results from mutations in the gene encoding acid
α-glucosidase (GAA) - an enzyme necessary for lysosomal glycogen hydrolysis. Hypoventilation and respiratory
insufficiency are prominent features of Pompe disease that result in respiratory failure in untreated infants.
Although breathing problems have traditionally been attributed to respiratory muscle and motor neuron
pathology, we recently described the significant role of smooth muscle (SM) pathology in the respiratory-
related morbidity of this disease. Currently, the only FDA approved therapy available to Pompe patients is
enzyme replacement therapy (ERT). ERT has significantly increased survival but as patients live longer, life
threatening SM pathology such as ruptured vascular aneurysms and airway weakness, has been unmasked.
The extent of residual SM involvement and cellular dysfunction following ERT remains unknown and will be a
focus of this project. In addition, we will study the efficacy of adeno-associated viral (AAV) gene therapy in
treating Pompe SM involvement. AAV gene therapy is ideal for monogenetic disorders such as Pompe disease,
however evidence of an AAV for infantile Pompe disease that targets SM, skeletal, cardiac and motor neurons
is still lacking. We propose a series of pre-clinical experiments that directly address SM lysosomal glycogen
accumulation in Pompe disease and explore the efficacy of AAV vectors in targeting all affected muscle groups
and motor neurons. We will focus on an AAV serotype and promoter that targets SM lysosomal glycogen
accumulation as well as cardiac, skeletal and motor neuron pathology in Pompe disease. Overall, the
fundamental hypothesis driving this proposal is that extensive smooth muscle glycogen accumulation
persists in Pompe disease despite ERT and that a novel AAV vector is necessary to treat smooth,
skeletal, cardiac, and motor neuron pathology. Our hypothesis has been formulated based on preliminary
data in the Pompe disease mouse model as well as clinical evidence seen in our Pompe disease patients. Three
specific aims will be accomplished using an established mouse model of Pompe disease: Aim 1: To
comprehensively examine respiratory and vascular SM involvement in Pompe disease and the impact of this
pathology on autophagic dysregulation. Aim 2: To compare early and late ERT on respiratory and vascular SM
function and glycogen accumulation. Aim 3: To examine the ability of a novel rationally designed AAV8g9-GAA
to effectively transduce and clear SM, skeletal muscle, and motor neuron glycogen accumulation in comparison
to AAV8 and AAV9. This project will address a gap in knowledge regarding smooth muscle dysfunction and will
identify the potential of a novel AAV therapy for infantile Pompe disease to significantly reduce morbidity and
mortality.

## Key facts

- **NIH application ID:** 10017695
- **Project number:** 5R01HD099486-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Mai ElMallah
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $348,356
- **Award type:** 5
- **Project period:** 2019-09-12 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10017695

## Citation

> US National Institutes of Health, RePORTER application 10017695, Targeted Therapy for Pompe Disease (5R01HD099486-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10017695. Licensed CC0.

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