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Journal article
Splice-Modulating Antisense Oligonucleotides as Therapeutics for Inherited Metabolic Diseases
BioDrugs : clinical immunotherapeutics, biopharmaceuticals, and gene therapy, Vol.38, pp.177-203
2024
PMID: 38252341
Abstract
The last decade (2013-2023) has seen unprecedented successes in the clinical translation of therapeutic antisense oligonucleotides (ASOs). Eight such molecules have been granted marketing approval by the United States Food and Drug Administration (US FDA) during the decade, after the first ASO drug, fomivirsen, was approved much earlier, in 1998. Splice-modulating ASOs have also been developed for the therapy of inborn errors of metabolism (IEMs), due to their ability to redirect aberrant splicing caused by mutations, thus recovering the expression of normal transcripts, and correcting the deficiency of functional proteins. The feasibility of treating IEM patients with splice-switching ASOs has been supported by FDA permission (2018) of the first "N-of-1" study of milasen, an investigational ASO drug for Batten disease. Although for IEM, owing to the rarity of individual disease and/or pathogenic mutation, only a low number of patients may be treated by ASOs that specifically suppress the aberrant splicing pattern of mutant precursor mRNA (pre-mRNA), splice-switching ASOs represent superior individualized molecular therapeutics for IEM. In this work, we first summarize the ASO technology with respect to its mechanisms of action, chemical modifications of nucleotides, and rational design of modified oligonucleotides; following that, we precisely provide a review of the current understanding of developing splice-modulating ASO-based therapeutics for IEM. In the concluding section, we suggest potential ways to improve and/or optimize the development of ASOs targeting IEM.
Details
- Title
- Splice-Modulating Antisense Oligonucleotides as Therapeutics for Inherited Metabolic Diseases
- Authors/Creators
- Suxiang Chen - Precision Nucleic Acid Therapeutics, Perron Institute for Neurological and Translational Science, Nedlands, WA, 6009, AustraliaSaumya Nishanga Heendeniya - Murdoch UniversityBao T Le - Murdoch UniversityKamal Rahimizadeh - Murdoch University, Centre for Molecular Medicine and Innovative TherapeuticsNavid Rabiee - Perron Institute for Neurological and Translational ScienceQurat Ul Ain Zahra - Murdoch University, Centre for Molecular Medicine and Innovative TherapeuticsRakesh N Veedu - Murdoch University, Centre for Molecular Medicine and Innovative Therapeutics
- Publication Details
- BioDrugs : clinical immunotherapeutics, biopharmaceuticals, and gene therapy, Vol.38, pp.177-203
- Publisher
- Springer Nature Switzerland AG
- Identifiers
- 991005631765607891
- Copyright
- © The Author(s) 2024
- Murdoch Affiliation
- Centre for Molecular Medicine and Innovative Therapeutics
- Language
- English
- Resource Type
- Journal article
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Highly Cited Paper
- Collaboration types
- Domestic collaboration
- Citation topics
- 2 Chemistry
- 2.170 Nucleic Acids Chemistry
- 2.170.988 Oligonucleotide Modifications
- Web Of Science research areas
- Immunology
- Oncology
- Pharmacology & Pharmacy
- ESI research areas
- Pharmacology & Toxicology