2018 Helen Walker Research Grant Award
International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste & Regional Coordinator Centre for Rare Diseases, Udine | Emanuele Buratti, PhD & Andrea Dardis, PhDAdvancing therapeutic strategies to correct RNA splicing defects in late-onset Pome disease.
Quick Facts
Year Awarded:
2018
Funding Amount:
$200,000
Lead Investigator:
Emanuele Buratti, PhD
Andrea Dardis, PhD
Institution:
International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy
Regional Coordinator Centre for Rare Diseases, University Hospital of Udine, Italy
Research Focus:
Therapeutic strategies to restore normal GAA RNA splicing in late-onset Pompe disease
Status:
Completed — Publications Added
Project Title
Pre-clinical validation of FDA-approved molecules able to rescue GAA pre-mRNA splicing of c.-32-13T>G mutants as therapeutic agents for late-onset Pompe disease
Project Snapshot
In 2018, the AMDA awarded the Helen Walker Research Grant to Emanuele Buratti, PhD and Andrea Dardis, PhD at the International Centre for Genetic Engineering and Biotechnology (ICGEB) in Trieste and the Regional Coordinator Centre for Rare Diseases in Udine, Italy to support a project focused on developing therapeutic strategies that correct RNA splicing defects in Pompe disease.
The goal of the project was to identify FDA-approved small molecules capable of restoring correct splicing of the GAA gene in patients carrying the common c.-32-13T>G mutation, a genetic variant responsible for many cases of late-onset Pompe disease. The team developed a fluorescent screening system to identify compounds that could improve exon 2 inclusion and increase functional enzyme activity in patient-derived cells.
Research Objectives
The project aimed to address several key questions related to treatment outcomes in Pompe disease:
1. Validate small molecules that restore correct GAA exon 2 splicing
The project sought to confirm whether the most promising compounds identified through high-throughput screening could reliably improve exon 2 inclusing in GAA transcripts carrying the c.-32-13T>G mutation. Experiments were designed to measure changes in RNA splicing and enzyme activity following treatment with candidate molecules.
2. Assess therapeutic effects in Pompe disease patient-derived muscle cells
Researchers planned to test the identified compounds in myotubes derived from patient muscle cells, which better mimic the biological environment of skeletal muscle affected by Pompe disease. These studies evaluated the effects of candidate molecules on GAA activity and glycogen storage in relevant disease models.
3. Identify molecular pathways involved in splicing correction
In addition to validating the lead compound, the team aimed to investigate the cellular pathways responsible for improved exon inclusion. Understanding the mechanism of action could help identify additional drugs that influence the same pathways and potentially enhance therapeutic outcomes.
Why This Matters
This research matters because many individuals with late-onset Pompe disease carry the c.-32-13T>G mutation which disrupts normal RNA splicing of the GAA gene and reduces production of the functional enzyme needed to break down glycogen. Even modest improvements in exon inclusion could significantly increase enzyme activity and improve disease outcomes.
By studying therapeutic approaches that restore correct RNA splicing, the team aimed to better understand how existing FDA-approved drugs might be repurposed to improve treatment strategies, clinical decision-making, and future research for people living with Pompe disease.
Research Team
Institution
International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy
Regional Coordinator Centre for Rare Diseases, University Hospital of Udine, Italy
Lead Investigator
Emanuele Buratti, PhD
Group Leader, Molecular Pathology Laboratory
Co-Investigator
Andrea Dardis, PhD
Head of Laboratory, Regional Coordinator Centre for Rare Diseases
Grant Support
The AMDA awarded $200,00 through the Helen Walker Research Grant to support this project.
Funding supported laboratory personnel, experimental materials and consumables, RNA sequencing analysis, and specialized muscle cell culture work needed to evaluate candidate therapeutic compounds.
Publications Resulting from This Research
”Deferoxamine
Citation:
Buratti E, Peruzzo P, Braga L, et al. Deferoxamine mesylate improves splicing and GAA activity of the common c.-32-13T>G allele in late-onset Pompe disease patient fibroblasts. Molecular Therapy: Methods & Clinical Development. 2021
Summary
This publication explores how the FDA-approved drug deferoxamine can improve RNA splicing of the GAA gene in cells carrying the c.-32-13T>G mutation. Treatment increased exon 2 inclusion and improved enzyme activity in patient fibroblasts, supporting the potential for drug repurposing approaches in Pompe disease.
Read the Article
https://amda-pompe.org/wp-content/uploads/2026/03/DEFEROXAMINE-MESYLATE-IMPROVES-SPLICING.pdf
Rescue of common and rare exon 2 skipping variants of the GAA gene using modified U1 snRNA
Citation:
Peruzzo P, Bergamin N, Bon M, et al. Rescue of common and rare exon 2 skipping variants of the GAA gene using modified U1 snRNA. Molecular Medicine. 2025.
Summary
This publication explores the use of engineered U1 snRNA molecules designed to restore correct RNA splicing of the GAA gene. The approach increased normal transcript production and improved enzyme activity in patient-derived cells, demonstrating a potential RNA-based therapeutic strategy for Pompe disease.
Read the Article
https://amda-pompe.org/wp-content/uploads/2026/03/RESCUE-OF-COMMON-AND-RARE-EXON.pdf
Related Outputs
- Follow-up studies investigating RNA splicing correction strategies in Pompe disease — 2021-2025
- Continued research on exon-2 splicing mechanisms in the GAA gene
Ongoing Impact
Research supported by the Helen Walker Research Grant helps build knowledge that can shape future studies, clinical care, and treatment strategies in Pompe disease. As additional publications, presentations, and follow-up work emerge, this page will continue to be updated.
About the Helen Walker Research Grant
The Helen Walker Research Grant honors Helen Walker, a dedicated patient advocate and leader in the Pompe community. Through this grant, the AMDA supports innovative research aimed at improving understanding, treatment, and care for individuals living with Pompe disease.
Explore more Helen Walker Research Grant awardees and the growing body of Pompe research supported by the AMDA.