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Deferoxamine mesylate improves splicing and GAA activity of the common c.-32-13T>G allele in late-onset PD patient fibroblasts

Research output: Contribution to journalArticlepeer-review

Emanuele Buratti, Paolo Peruzzo, Luca Braga, Irene Zanin, Cristiana Stuani, Elisa Goina, Maurizio Romano, Mauro Giacca, Andrea Dardis

Original languageEnglish
Pages (from-to)227-236
Number of pages10
JournalMolecular Therapy - Methods and Clinical Development
Published12 Mar 2021

Bibliographical note

Funding Information: This work was supported by Telethon grant GGP14192 , AFM-Telethon Project SPLICESCREENPD, Helen Walker Research Grant for Pompe Disease from the Acid Maltase Deficiency Association (AMDA), and the Associazione Italiana Glicogenosi (AIG). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: © 2020 The Authors Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors


Pompe disease (PD) is an autosomal recessive lysosomal storage disorder due to deficient activity of the acid alpha glucosidase enzyme (GAA). As a consequence of the enzymatic defect, undigested glycogen accumulates within lysosomes. Most patients affected by the late-onset (LO) phenotype carry in at least one allele the c.-32-13T>G variant, which leads to exon 2 exclusion from the pre-mRNA. These patients display a variable and suboptimal response to enzyme replacement therapy. To identify novel therapeutic approaches, we developed a fluorescent GAA exon 2 splicing assay and screened a library of US Food and Drug Administration (FDA)-approved compounds. This led to the identification of several drugs able to restore normal splicing. Among these, we further validated the effects of the iron chelator deferoxamine (Defe) in c.-32-13T>G fibroblasts. Defe treatment resulted in a 2-fold increase of GAA exon 2 inclusion and a 40% increase in enzymatic activity. Preliminary results suggest that this effect is mediated by the regulation of iron availability, at least partially. RNA-seq experiments also showed that Defe might shift the balance of splicing factor levels toward a profile promoting GAA exon 2 inclusion. This work provides the basis for drug repurposing and development of new chemically modified molecules aimed at improving the clinical outcome in LO-PD patients.

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