# Antisense oligonucleotide treatment for Pompe disease

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA-IRVINE · 2023 · $172,700

## Abstract

Project Abstract:
Pompe disease is a devastating myopathy resulting from the deficiency of the lysosomal enzyme acid alpha-
glucosidase (GAA),resulting in accumulation of glycogen in lysosomes and cytoplasm. The standard of care is
enzyme replacement therapy (ERT) with recombinant human (rh) GAA. Patients with Pompe disease often have
poor outcomes due to limited efficacy of the drug in clearing muscle glycogen stores. Substrate Reduction
Therapy (SRT) is effective in other lysosomal storage diseases such as Gaucher and Fabry disease. We propose
that by knocking down glycogen synthase (GSY1), we will reduce glycogen synthesis in muscle, thus reducing
the amount of substrate requiring to be cleared by enzyme. Our long-term goal is to develop a potent therapy
to stop/reduce the progression of the muscle disease in Pompe disease. Major gaps: Despite ERT, patients
continue to accumulate glycogen in lysosomes leading to muscle fibrosis and fatty replacement. Effective therapy
for the progressive muscle weakness of Pompe disease is thus a huge unmet need. Preliminary results:
Antisense Oligonucleotides (ASO) technology has emerged as a powerful direct therapeutic alternative to
conventional small molecule approaches or gene replacement strategies for the treatment of genetic disorders
such as spinal muscular atrophy. ASOs are short, synthetic single-stranded DNA sequences designed to target
RNA by well-characterized Watson-Crick base pairing, and once bound to the target RNA, can modulate RNA
function through a degradative mechanism using RnaseH1. Ionis Pharmaceuticals designed and screened ASOs
targeting mouse GYS1 in vitro to identify the most efficacious ASO. The lead ASOs from the screen were
validated in a dose response study and the top 10 ASOs were screened for testing in wild type mice. Three
GYS1 ASOs showed the best tolerability and efficacy profile leading to knock down of GYS1 mRNA by
approximately 50% of control. Preclinical studies of the effects of the GYS1 ASOs 25 mg/kg/weekly on muscle
glycogen, histology, and muscle function in 1 month and 3-month-old Pompe mice indicated that GYS1 ASOs
were effective in knocking down GYS1 by approximately 85%, with approximately 50% improvement in clearing
muscle glycogen levels. We therefore believe that early reduction of glycogen substrate or a combination therapy
with ERT may be the key to successful treatment in Pompe disease. Hypothesis: We propose that GYS1 ASOs
in Pompe mice will reduce glycogen production and prevent muscle weakness, either as monotherapy if started
early, or in combination with ERT, to obtain maximum therapeutic benefit. Specific Aims: Aim 1: Identification
of the most effective ASO-mediated glycogen synthase (GYS1) knock down to prevent glycogen accumulation
in a mouse model of Pompe disease. Aim 2: Correction of muscle glycogen and weakness using GYS1
antisense oligonucleotides in combination with Enzyme Replacement Therapy (ERT) in Pompe mice. Success
with this translati...

## Key facts

- **NIH application ID:** 10652582
- **Project number:** 5R21AR080972-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** VIRGINIA Eunice KIMONIS
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $172,700
- **Award type:** 5
- **Project period:** 2022-07-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10652582

## Citation

> US National Institutes of Health, RePORTER application 10652582, Antisense oligonucleotide treatment for Pompe disease (5R21AR080972-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10652582. Licensed CC0.

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