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 (GAA) 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...
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| Language: | English |
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Elsevier
2025-06-01
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| Series: | Molecular Therapy: Nucleic Acids |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253125000782 |
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| author | Ryan A. Oliver Meghan E. Ahern Perla G. Castaneda Tushare Jinadasa Anirban Bardhan Kathy Y. Morgan Kristin Ha Kailash Adhikari Nino Jungels Noa Liberman Anindita Mitra Christopher D. Greer Alec M. Wright Emily G. Thompson Stephanie Garcia Elena Copson Senkara Allu Xuyu Tan Alex J. Callahan Bao Zhong Cai Vincent Guerlavais Kevin J. Kim Annika B. Malmberg |
| author_facet | Ryan A. Oliver Meghan E. Ahern Perla G. Castaneda Tushare Jinadasa Anirban Bardhan Kathy Y. Morgan Kristin Ha Kailash Adhikari Nino Jungels Noa Liberman Anindita Mitra Christopher D. Greer Alec M. Wright Emily G. Thompson Stephanie Garcia Elena Copson Senkara Allu Xuyu Tan Alex J. Callahan Bao Zhong Cai Vincent Guerlavais Kevin J. Kim Annika B. Malmberg |
| author_sort | Ryan A. Oliver |
| collection | DOAJ |
| description | Late-onset Pompe disease (LOPD) is overwhelmingly caused by a single mutation that disrupts splicing of acid-alpha glucosidase (GAA) 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 Gaa 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 GAA 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. |
| format | Article |
| id | doaj-art-e322a43ac2fe4070bb85945362ef0a20 |
| institution | OA Journals |
| issn | 2162-2531 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj-art-e322a43ac2fe4070bb85945362ef0a202025-08-20T02:16:29ZengElsevierMolecular Therapy: Nucleic Acids2162-25312025-06-0136210252410.1016/j.omtn.2025.102524Splicing correction by peptide-conjugated morpholinos as a novel treatment for late-onset Pompe diseaseRyan A. Oliver0Meghan E. Ahern1Perla G. Castaneda2Tushare Jinadasa3Anirban Bardhan4Kathy Y. Morgan5Kristin Ha6Kailash Adhikari7Nino Jungels8Noa Liberman9Anindita Mitra10Christopher D. Greer11Alec M. Wright12Emily G. Thompson13Stephanie Garcia14Elena Copson15Senkara Allu16Xuyu Tan17Alex J. Callahan18Bao Zhong Cai19Vincent Guerlavais20Kevin J. Kim21Annika B. Malmberg22Sarepta Therapeutics, Inc, 215 First Street, Cambridge, MA 02142, USASarepta Therapeutics, Inc, 215 First Street, Cambridge, MA 02142, USASarepta Therapeutics, Inc, 215 First Street, Cambridge, MA 02142, USASarepta Therapeutics, Inc, 215 First Street, Cambridge, MA 02142, USASarepta Therapeutics, Inc, 215 First Street, Cambridge, MA 02142, USASarepta Therapeutics, Inc, 215 First Street, Cambridge, MA 02142, USA; Corresponding author: Kathy Y. Morgan, Sarepta Therapeutics, Inc, 215 First Street, Cambridge, MA 02142, USA.Sarepta Therapeutics, Inc, 215 First Street, Cambridge, MA 02142, USASarepta Therapeutics, Inc, 215 First Street, Cambridge, MA 02142, USASarepta Therapeutics, Inc, 215 First Street, Cambridge, MA 02142, USASarepta Therapeutics, Inc, 215 First Street, Cambridge, MA 02142, USASarepta Therapeutics, Inc, 215 First Street, Cambridge, MA 02142, USASarepta Therapeutics, Inc, 215 First Street, Cambridge, MA 02142, USASarepta Therapeutics, Inc, 215 First Street, Cambridge, MA 02142, USASarepta Therapeutics, Inc, 215 First Street, Cambridge, MA 02142, USASarepta Therapeutics, Inc, 215 First Street, Cambridge, MA 02142, USASarepta Therapeutics, Inc, 215 First Street, Cambridge, MA 02142, USASarepta Therapeutics, Inc, 215 First Street, Cambridge, MA 02142, USASarepta Therapeutics, Inc, 215 First Street, Cambridge, MA 02142, USASarepta Therapeutics, Inc, 215 First Street, Cambridge, MA 02142, USASarepta Therapeutics, Inc, 215 First Street, Cambridge, MA 02142, USASarepta Therapeutics, Inc, 215 First Street, Cambridge, MA 02142, USASarepta Therapeutics, Inc, 215 First Street, Cambridge, MA 02142, USASarepta Therapeutics, Inc, 215 First Street, Cambridge, MA 02142, USALate-onset Pompe disease (LOPD) is overwhelmingly caused by a single mutation that disrupts splicing of acid-alpha glucosidase (GAA) 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 Gaa 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 GAA 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.http://www.sciencedirect.com/science/article/pii/S2162253125000782MT: Oligonucleotides: Therapies and Applicationslate-onset Pompe diseaselysosomal storage diseaseoligonucleotide therapeuticsRNA medicinessplice switching antisense oligonucleotide |
| spellingShingle | Ryan A. Oliver Meghan E. Ahern Perla G. Castaneda Tushare Jinadasa Anirban Bardhan Kathy Y. Morgan Kristin Ha Kailash Adhikari Nino Jungels Noa Liberman Anindita Mitra Christopher D. Greer Alec M. Wright Emily G. Thompson Stephanie Garcia Elena Copson Senkara Allu Xuyu Tan Alex J. Callahan Bao Zhong Cai Vincent Guerlavais Kevin J. Kim Annika B. Malmberg Splicing correction by peptide-conjugated morpholinos as a novel treatment for late-onset Pompe disease Molecular Therapy: Nucleic Acids MT: Oligonucleotides: Therapies and Applications late-onset Pompe disease lysosomal storage disease oligonucleotide therapeutics RNA medicines splice switching antisense oligonucleotide |
| title | Splicing correction by peptide-conjugated morpholinos as a novel treatment for late-onset Pompe disease |
| title_full | Splicing correction by peptide-conjugated morpholinos as a novel treatment for late-onset Pompe disease |
| title_fullStr | Splicing correction by peptide-conjugated morpholinos as a novel treatment for late-onset Pompe disease |
| title_full_unstemmed | Splicing correction by peptide-conjugated morpholinos as a novel treatment for late-onset Pompe disease |
| title_short | Splicing correction by peptide-conjugated morpholinos as a novel treatment for late-onset Pompe disease |
| title_sort | splicing correction by peptide conjugated morpholinos as a novel treatment for late onset pompe disease |
| topic | MT: Oligonucleotides: Therapies and Applications late-onset Pompe disease lysosomal storage disease oligonucleotide therapeutics RNA medicines splice switching antisense oligonucleotide |
| url | http://www.sciencedirect.com/science/article/pii/S2162253125000782 |
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