Splicing correction by peptide-conjugated morpholinos as a novel treatment for late-onset Pompe disease

Late-onset Pompe disease (LOPD) is overwhelmingly caused by a single mutation that disrupts splicing of acid-alpha glucosidase (<i>GAA</i>) and results in the accumulation of lysosomal glycogen in muscle cells leading to progressive muscle weakness in patients. Current therapeutics for LOPD do not meet the needs of patients and have largely been developed in mutant animal models lacking <i>Gaa</i> expression, which more closely mimic the less common infantile form of the disease. Here we design and evaluate peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) to target the causative mutation in <i>GAA</i> and correct pathogenic splicing in muscle tissue. We show PPMO compounds correct LOPD splicing in both patient induced pluripotent stem cell-derived muscle cells and in skeletal muscle tissue after intravenous dosing in a newly developed humanized LOPD animal model that recapitulates patient LOPD splicing.

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Journal
Molecular Therapy — Nucleic Acids
Published
2025-03-27
DOI
https://doi.org/10.1016/j.omtn.2025.102524
Primary Topic
Lysosomal Storage Disorders Research
Type
article
Field-Weighted Citation Impact
0.00

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article

Splicing correction by peptide-conjugated morpholinos as a novel treatment for late-onset Pompe disease

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Molecular Therapy — Nucleic Acids
Lysosomal Storage Disorders Research
article

Splicing correction by peptide-conjugated morpholinos as a novel treatment for late-onset Pompe disease

Alex J. Callahan, Stephanie Garcia, Kathy Ye Morgan, Perla Castaneda, Kristin Ha, Ryan A. Oliver, Srinivasa Rao Allu, Vincent Guerlavais, Emily G. Thompson, Ellen Copson, Anirban Bardhan, Anindita Mitra, Alec M. Wright, Meghan E. Ahern, Kevin J. Kim, Christopher Greer, Annika B. Malmberg, Xuyu Tan, Tushare Jinadasa, Nino Jungels, Kailash Adhikari, Bao Zhong Cai, Noa Liberman
article en

Abstract

Late-onset Pompe disease (LOPD) is overwhelmingly caused by a single mutation that disrupts splicing of acid-alpha glucosidase (<i>GAA</i>) and results in the accumulation of lysosomal glycogen in muscle cells leading to progressive muscle weakness in patients. Current therapeutics for LOPD do not meet the needs of patients and have largely been developed in mutant animal models lacking <i>Gaa</i> expression, which more closely mimic the less common infantile form of the disease. Here we design and evaluate peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) to target the causative mutation in <i>GAA</i> and correct pathogenic splicing in muscle tissue. We show PPMO compounds correct LOPD splicing in both patient induced pluripotent stem cell-derived muscle cells and in skeletal muscle tissue after intravenous dosing in a newly developed humanized LOPD animal model that recapitulates patient LOPD splicing.

Molecular Therapy — Nucleic AcidsVol. 36(2)
Sarepta Therapeutics (United States) (US)
Sarepta Therapeutics
Zero hunger
Openalex Percentile: Top 93%
Lysosomal Storage Disorders Research
DOIOpen Access PDFOpenAlex
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