Abstract
Duchenne muscular dystrophy (DMD) is the most common childhood neuromuscular disorder. It is caused by mutations in the DMD gene that disrupt the open reading frame (ORF) preventing the production of functional dystrophin protein. The loss of dystrophin ultimately leads to the degeneration of muscle fibres, progressive weakness and premature death. Antisense oligonucleotides (AOs) targeted to splicing elements within DMD pre-mRNA can induce the skipping of targeted exons, restoring the ORF and the consequent production of a shorter but functional dystrophin protein. This approach may lead to an effective disease modifying treatment for DMD and progress towards clinical application has been rapid. Less than a decade has passed between the first studies published in 1998 describing the use of AOs to modify the DMD gene in mice and the results of the first intramuscular proof of concept clinical trials. Whilst phase II and III trials are now underway, the heterogeneity of DMD mutations, efficient systemic delivery and targeting of AOs to cardiac muscle remain significant challenges. Here we review the current status of AO-mediated therapy for DMD, discussing the preclinical, clinical and regulatory hurdles and their possible solutions to expedite the translation of AO-mediated exon skipping therapy to clinic.
Keywords: Antisense oligonucleotides, clinical trials, duchenne muscular dystrophy, becker muscular dystrophy, dystrophin, exon skipping, RNA therapy, BMD, PMO, DMD
Current Gene Therapy
Title:Antisense Oligonucleotide-Mediated Exon Skipping for Duchenne Muscular Dystrophy: Progress and Challenges
Volume: 12 Issue: 3
Author(s): Virginia Arechavala-Gomeza, Karen Anthony, Jennifer Morgan and Francesco Muntoni
Affiliation:
Keywords: Antisense oligonucleotides, clinical trials, duchenne muscular dystrophy, becker muscular dystrophy, dystrophin, exon skipping, RNA therapy, BMD, PMO, DMD
Abstract: Duchenne muscular dystrophy (DMD) is the most common childhood neuromuscular disorder. It is caused by mutations in the DMD gene that disrupt the open reading frame (ORF) preventing the production of functional dystrophin protein. The loss of dystrophin ultimately leads to the degeneration of muscle fibres, progressive weakness and premature death. Antisense oligonucleotides (AOs) targeted to splicing elements within DMD pre-mRNA can induce the skipping of targeted exons, restoring the ORF and the consequent production of a shorter but functional dystrophin protein. This approach may lead to an effective disease modifying treatment for DMD and progress towards clinical application has been rapid. Less than a decade has passed between the first studies published in 1998 describing the use of AOs to modify the DMD gene in mice and the results of the first intramuscular proof of concept clinical trials. Whilst phase II and III trials are now underway, the heterogeneity of DMD mutations, efficient systemic delivery and targeting of AOs to cardiac muscle remain significant challenges. Here we review the current status of AO-mediated therapy for DMD, discussing the preclinical, clinical and regulatory hurdles and their possible solutions to expedite the translation of AO-mediated exon skipping therapy to clinic.
Export Options
About this article
Cite this article as:
Arechavala-Gomeza Virginia, Anthony Karen, Morgan Jennifer and Muntoni Francesco, Antisense Oligonucleotide-Mediated Exon Skipping for Duchenne Muscular Dystrophy: Progress and Challenges, Current Gene Therapy 2012; 12 (3) . https://dx.doi.org/10.2174/156652312800840621
DOI https://dx.doi.org/10.2174/156652312800840621 |
Print ISSN 1566-5232 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5631 |
Call for Papers in Thematic Issues
Programmed Cell Death Genes in Oncology: Pioneering Therapeutic and Diagnostic Frontiers (BMS-CGT-2024-HT-45)
Programmed Cell Death (PCD) is recognized as a pivotal biological mechanism with far-reaching effects in the realm of cancer therapy. This complex process encompasses a variety of cell death modalities, including apoptosis, autophagic cell death, pyroptosis, and ferroptosis, each of which contributes to the intricate landscape of cancer development and ...read more
Related Journals
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Targeting Mitochondrial Dysfunction in Chronic Heart Failure: Current Evidence and Potential Approaches
Current Pharmaceutical Design Circulating Biomarkers for the Diagnosis and Prognosis of Heart Failure
Current Medicinal Chemistry Perioperative Management of Obese Parturients
Current Women`s Health Reviews Pharmacotherapy of Aortic Stenosis-Success or Failure?
Current Pharmaceutical Biotechnology New Targeted Therapies for Thyroid Cancer
Current Genomics Targeting SUMOylation Cascade for Diabetes Management
Current Drug Targets Organoselenium Compounds as Potential Therapeutic and Chemopreventive Agents: A Review
Current Medicinal Chemistry Transient Receptor Potential (TRP) Channels and Cardiac Fibrosis
Current Topics in Medicinal Chemistry Mutations of Mitochondrial DNA in Atherosclerosis and Atherosclerosis-Related Diseases
Current Pharmaceutical Design Antiapoptotic Effect of Novel Compound from Herba leonuri-Leonurine (SCM-198): A Mechanism Through Inhibition of Mitochondria Dysfunction in H9c2 Cells
Current Pharmaceutical Biotechnology Dynamic Ventricular Repolarisation: From Physiology to Prognosis
Current Cardiology Reviews Candidate Circulating Biomarkers for the Cardiovascular Disease Continuum
Current Pharmaceutical Design Anti-HER2 Cancer Therapy and Cardiotoxicity
Current Pharmaceutical Design Respiratory Syncytial Virus (RSV) Prevention and Treatment: Past, Present, and Future
Cardiovascular & Hematological Agents in Medicinal Chemistry Sirtuins: Possible Clinical Implications in Cardio and Cerebrovascular Diseases
Current Drug Targets Developments in Imaging Technologies Related to Hypertensive Cardiovascular Diseases
Current Pharmaceutical Design Surgical Ventricular Restoration to Reverse Left Ventricular Remodeling
Current Cardiology Reviews Calcium Channel Blockers in Obesity-Related Hypertension
Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Discontinued) A Review of Chinese Herbal Medicine for the Treatment of Chronic Heart Failure
Current Pharmaceutical Design Cardioembolic Stroke: Clinical Features, Specific Cardiac Disorders and Prognosis
Current Cardiology Reviews