Duchenne Muscular Dystrophy: Molecular Mechanisms of Disease and Gene Therapy Strategies

David Aphkhazava; Maia Nozadze; Levan Gulua; Mzia Tsiklauri; Manana Makharadze; Maia Berodze; Nodar Sulashvili; Giorgi Margvelani; Tamuna Samadashvili; Nino Maziashvili; Lolita Shengelia; Madiha Thasneem; Rania Thowfeeq Shaikh; George Maglakelidze; Ilia Atanelishvili

Authors

David Aphkhazava PhD, Professor, University of Georgia, Tbilisi, Georgia. Orcid: https://orcid.org/0000- 0001- 6216-64
Maia Nozadze PhD, Professor, University of Georgia, Tbilisi, Georgia
Levan Gulua PhD, Professor, Head of bachelor program of Biomedicine at University of Georgia, Tbilisi, Georgia
Mzia Tsiklauri PhD, Affiliated Professor of the Medical Programs of Gr.Robakidze University, Microbiology, Immunology, Virology, Infection Control. Invited Professor of the Medical Programs of Alte University, Tbilisi, Georgia. Invited Professor of the Medical Programs of Caucasus International University, Laboratory Medicine, Tbilisi, Georgia. Member of the Georgian Immunologists Association, Member of the Accreditation Council of the Quality Development, Center of the Ministry of Education of Georgia
Manana Makharadze Prof. David Agmashenebeli University of Georgia, Tbilisi, Georgia
Maia Berodze Assistant Professor at Caucasus International University, Tbilisi, Georgia
Nodar Sulashvili MD, PhD, Doctor of Pharmaceutical and Pharmacological Sciences In Medicine, Invited Lecturer (Professor) of Scientific Research-Skills Center at Tbilisi State Medical University; Professor of Medical and Clinical Pharmacology of International School of Medicine at Alte University; Professor of Pharmacology of Faculty of Medicine at Georgian National University SEU, Associate Affiliated Professor of Medical Pharmacology of Faculty of Medicine at Sulkhan-Saba Orbeliani University; Associate Professor of Medical Pharmacology at School of Medicine at David Aghmashenebeli University of Georgia; Associate Professor of Biochemistry and Pharmacology Direction of School of Health Sciences at the University of Georgia. Associate Professor of Pharmacology of Faculty Dentistry and Pharmacy at Tbilisi Humanitarian Teaching University; Tbilisi, Georgia; Orcid: https://orcid.org/0000-0002-9005-8577.
Giorgi Margvelani Prof. European University, Tbilisi, Georgia
Tamuna Samadashvili University of Georgia, Tbilisi, Georgia
Nino Maziashvili Associate Professor, University of Georgia, Tamar Gagoshidze Neuropsychology Center, Tbilisi, Georgia
Lolita Shengelia PhD, Invited lecturer of Georgian National University, Tbilisi, Georgia; Invited lecturer of Georgian American University, Tbilisi, Georgia
Madiha Thasneem University of Georgia, Tbilisi, Georgia
Rania Thowfeeq Shaikh Ivane Javakhishvili Tbilisi State University, Tbilisi, Georgia
George Maglakelidze PhD, Professor, University of Georgia, Tbilisi, Georgia
Ilia Atanelishvili Medical University of South Carolina, Charleston, SC, USA

Keywords:

Duchenne muscular dystrophy, dystrophin, molecular pathogenesis, exon skipping, micro-dystrophin, AAV gene therapy, CRISPR/Cas9, genome editing

Abstract

Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular disorder caused by loss-of-function mutations in the DMD gene and the consequent absence or major truncation of dystrophin. The disease is fundamentally a disorder of membrane instability: without dystrophin, the sarcolemma becomes mechanically fragile during contraction, allowing abnormal calcium influx, mitochondrial dysfunction, protease activation, oxidative injury, and chronic inflammatory signaling. Repeated myofibre damage eventually exhausts regenerative capacity and drives progressive fibrosis and fatty replacement, producing the characteristic trajectory of skeletal muscle weakness, loss of ambulation, respiratory insufficiency, and cardiomyopathy. Recent therapeutic development has shifted from supportive management alone toward direct molecular intervention. Mutation-specific exon skipping seeks to restore the reading frame and convert a Duchenne-like transcript into a Becker-like transcript that yields internally truncated but partially functional dystrophin. AAV-mediated micro-dystrophin gene replacement addresses the challenge of the large native DMD coding sequence by delivering engineered miniaturized constructs that preserve essential functional domains. Genome-editing approaches, particularly CRISPR/Cas9-based strategies, pursue permanent correction at the DNA level through exon excision or splice-site reframing. Together, these approaches illustrate a transition from symptom modulation to mechanism-directed therapy. Their promise, however, is balanced by major translational challenges, including limited dystrophin restoration with first-generation exon-skipping agents, immune barriers to viral delivery, uncertain long-term durability of episomal expression, inability to re-dose AAV efficiently, and unresolved delivery and safety issues for genome editing. This focused article synthesizes the molecular basis of DMD and the principal gene-therapy strategies currently shaping the field.

Duchenne Muscular Dystrophy: Molecular Mechanisms of Disease and Gene Therapy Strategies

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