# Control of Breathing and Pompe Disease

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2022 · $593,203

## Abstract

Project Summary / Abstract:
Pompe disease results from mutations in the gene for acid α-glucosidase (GAA) – an enzyme necessary to
degrade lysosomal glycogen. Early-onset disease occurs in the absence of functional GAA which leads to
cardiorespiratory failure early in life. Late-onset disease is associated with reduced GAA activity and gradual
progression to respiratory failure. Work from our first two grant cycles indicates neural involvement in
respiratory failure in Gaa-/- mice and Pompe patients. This is relevant since the standard of care – intravenous
enzyme therapy using recombinant GAA - does not reach the central nervous system (CNS) and patients still
progress to respiratory failure. Our overarching hypothesis is that adeno-associated virus (AAV) therapy is
capable of restoring life-long GAA expression throughout the CNS, skeletal and cardiac muscle, thereby
preserving cardiorespiratory function and prolonging life. Aim 1 focuses on AAV therapy for early-onset
disease which requires early life treatments that can prevent both respiratory and cardiac failure. To better
study this problem, we created a Gaa null (Gaa-/-) rat model which recapitulates the early onset phenotype with
cardiorespiratory pathology and early mortality. Preliminary data indicate that neonatal AAV-GAA therapy
(desmin promoter, AAV9 serotype) evokes no detectable immune response, mitigates cardiac and respiratory
pathology and prevents early death. Thus, we hypothesize that a single intravenous AAV-GAA dose in young
rats can drive persistent and widespread GAA expression and extend the Pompe rat lifespan. Aim 2
addresses late onset Pompe disease in which respiratory failure is the primary cause of mortality. Based on
data from our first two grant cycles we hypothesize that neural directed AAV-GAA therapy in adult Pompe rats
is sufficient to prevent respiratory decline and extend the lifespan. By packaging AAV-GAA with muscle
(creatine kinase 8), neural (synapsin) or tissue specific (muscle and neural, desmin) promoters, and delivering
the vector intrathecally, intravenously, or both, we can drive GAA expression in a manner that will determine if
neural correction is necessary and sufficient to prevent decline. The aforementioned Gaa null rat will be used
to test proof-of-concept for neural vs. muscle correction in the absence of endogenous GAA activity. We will
also use another new Pompe rat model in which CRISPR/cas9 has been used to insert the most common
human gene mutation causing late-onset Pompe disease (IVS1) into the rat genome. This is important
because the IVS1 mutation leads to low but not absent GAA activity and is associated with delayed
progression to respiratory failure. The proposed work is significant because current therapeutic strategies in
Pompe disease only delay disease progression with eventual respiratory failure. The strategies proposed here
will also contribute to the broader goal of advancing gene therapy for neurodegenerative conditions a...

## Key facts

- **NIH application ID:** 10394231
- **Project number:** 5R01HD052682-13
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** BARRY J BYRNE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $593,203
- **Award type:** 5
- **Project period:** 2007-02-15 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10394231

## Citation

> US National Institutes of Health, RePORTER application 10394231, Control of Breathing and Pompe Disease (5R01HD052682-13). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10394231. Licensed CC0.

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