Abstract
In little more than a decade, induced exon skipping as a therapy to treat Duchenne muscular dystrophy (DMD) has progressed from a concept tested in vitro, to pre-clinical evaluation in mouse and dog models, and recent completion of Phase I clinical trials in man. There is no longer any doubt that antisense oligomers can redirect dystrophin gene processing and by-pass protein truncating mutations after direct injection into muscle. Proof-of-concept has been demonstrated in human dystrophic muscle, with trials in Leiden and London showing that two different oligomer chemistries can restore the reading-frame in selected DMD patients by excising dystrophin exon 51. Systemic delivery of both oligomer types into DMD patients has commenced with promising results but it remains to be established if this therapy will have measurable clinical benefits. Targeted removal of exon 51 will only be directly applicable to about one in ten DMD individuals, and the immediate challenges include development of appropriate and effective delivery regimens, and extending spliceswitching therapies to other dystrophin gene lesions. The success of induced exon skipping has spawned a number of “fusion therapies”, including vector-mediated dystrophin exon skipping and ex vivo viral delivery of splice-switching antisense molecules into myogenic stem cells, followed by implantation, which may address long term oligomer delivery issues. This review summarizes the pivotal events leading to the completion of the first proof-of-concept trials and speculates on some of the scientific, ethical, regulatory and commercial challenges facing targeted exon skipping for the treatment of DMD.
Keywords: Duchenne muscular dystrophy, Becker muscular dystrophy, Dystrophin, Antisense oligomer, Exon skipping, Molecular medicine
Current Pharmaceutical Design
Title: Splice Modification to Restore Functional Dystrophin Synthesis in Duchenne Muscular Dystrophy
Volume: 16 Issue: 8
Author(s): Steve. D. Wilton and Susan Fletcher
Affiliation:
Keywords: Duchenne muscular dystrophy, Becker muscular dystrophy, Dystrophin, Antisense oligomer, Exon skipping, Molecular medicine
Abstract: In little more than a decade, induced exon skipping as a therapy to treat Duchenne muscular dystrophy (DMD) has progressed from a concept tested in vitro, to pre-clinical evaluation in mouse and dog models, and recent completion of Phase I clinical trials in man. There is no longer any doubt that antisense oligomers can redirect dystrophin gene processing and by-pass protein truncating mutations after direct injection into muscle. Proof-of-concept has been demonstrated in human dystrophic muscle, with trials in Leiden and London showing that two different oligomer chemistries can restore the reading-frame in selected DMD patients by excising dystrophin exon 51. Systemic delivery of both oligomer types into DMD patients has commenced with promising results but it remains to be established if this therapy will have measurable clinical benefits. Targeted removal of exon 51 will only be directly applicable to about one in ten DMD individuals, and the immediate challenges include development of appropriate and effective delivery regimens, and extending spliceswitching therapies to other dystrophin gene lesions. The success of induced exon skipping has spawned a number of “fusion therapies”, including vector-mediated dystrophin exon skipping and ex vivo viral delivery of splice-switching antisense molecules into myogenic stem cells, followed by implantation, which may address long term oligomer delivery issues. This review summarizes the pivotal events leading to the completion of the first proof-of-concept trials and speculates on some of the scientific, ethical, regulatory and commercial challenges facing targeted exon skipping for the treatment of DMD.
Export Options
About this article
Cite this article as:
Wilton D. Steve. and Fletcher Susan, Splice Modification to Restore Functional Dystrophin Synthesis in Duchenne Muscular Dystrophy, Current Pharmaceutical Design 2010; 16 (8) . https://dx.doi.org/10.2174/138161210790883480
DOI https://dx.doi.org/10.2174/138161210790883480 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
Call for Papers in Thematic Issues
"Tuberculosis Prevention, Diagnosis and Drug Discovery"
The Nobel Prize-winning discoveries of Mycobacterium tuberculosis and streptomycin have enabled an appropriate diagnosis and an effective treatment of tuberculosis (TB). Since then, many newer diagnosis methods and drugs have been saving millions of lives. Despite advances in the past, TB is still a leading cause of infectious disease mortality ...read more
Current Pharmaceutical challenges in the treatment and diagnosis of neurological dysfunctions
Neurological dysfunctions (MND, ALS, MS, PD, AD, HD, ALS, Autism, OCD etc..) present significant challenges in both diagnosis and treatment, often necessitating innovative approaches and therapeutic interventions. This thematic issue aims to explore the current pharmaceutical landscape surrounding neurological disorders, shedding light on the challenges faced by researchers, clinicians, and ...read more
Emerging and re-emerging diseases
Faced with a possible endemic situation of COVID-19, the world has experienced two important phenomena, the emergence of new infectious diseases and/or the resurgence of previously eradicated infectious diseases. Furthermore, the geographic distribution of such diseases has also undergone changes. This context, in turn, may have a strong relationship with ...read more
Melanoma and Non-Melanoma Skin Cancer Treatment: Standard of Care and Recent Advances
In this thematic issue, we aim to provide a standard of care of the diagnosis and treatment of melanoma and non-melanoma skin cancer. The editor will invite authors from different countries who will write review articles of melanoma and non-melanoma skin cancers. The Diagnosis, Staging, Surgical Treatment, Non-Surgical Treatment all ...read more
- 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
-
Urotensin-II Receptor: A Double Identity Receptor Involved in Vasoconstriction and in the Development of Digestive Tract Cancers and other Tumors
Current Cancer Drug Targets Triple Threat: The Na+/Ca2+ Exchanger in the Pathophysiology of Cardiac Arrhythmia, Ischemia and Heart Failure
Current Drug Targets Advances in Chagas Disease Chemotherapy
Anti-Infective Agents in Medicinal Chemistry Anti-infective and Antineoplastic Properties of Green Tea Catechins: Examining the Therapeutic Risk-benefit Ratio
Current Nutraceuticals Regulation of Self-Reactive T Cells by Human Immunoglobulins- Implications for Multiple Sclerosis Therapy
Current Pharmaceutical Design Emerging Concepts for Myocardial Late Gadolinium Enhancement MRI
Current Cardiology Reviews The Medicinal Chemistry of Genus <i>Aralia</i>
Current Topics in Medicinal Chemistry Beta-adrenergic Signaling: Complexities and Therapeutic Relevance to Heart Failure
Current Signal Transduction Therapy Role of Heme Oxygenase-1 in Cardiovascular Function
Current Pharmaceutical Design Cross-Talk Between Adipose Tissue Health, Myocardial Metabolism and Vascular Function: The Adipose-Myocardial and Adipose-Vascular Axes
Current Pharmaceutical Design Targeting Cyclooxygenase and Nitric Oxide Pathway Cross-Talk: A New Signal Transduction Pathway for Developing More Effective Anti- Inflammatory Drugs
Current Signal Transduction Therapy The Role of Aryl Hydrocarbon Receptor-Regulated Cytochrome P450 Enzymes in Glioma
Current Pharmaceutical Design Recreational Drug Misuse and Stroke
Current Drug Abuse Reviews Susceptibility Genes in Hypertension
Current Pharmaceutical Design Diallyl Sulfide: Potential Use in Novel Therapeutic Interventions in Alcohol, Drugs, and Disease Mediated Cellular Toxicity by Targeting Cytochrome P450 2E1
Current Drug Metabolism Targeting mTOR Signaling in Type 2 Diabetes Mellitus and Diabetes Complications
Current Drug Targets Obesity and Pregnancy
Current Women`s Health Reviews Impact of RET Screening on the Management of Multiple Endocrine Neoplasia Type 2A: 10 Years Experience and Follow-Up in Three Families
Endocrine, Metabolic & Immune Disorders - Drug Targets Pure Polyphenols Applications for Cardiac Health and Disease
Current Pharmaceutical Design Meet Our Editorial Board Member:
Applied Clinical Research, Clinical Trials and Regulatory Affairs