Gene Therapy Outcomes in Duchenne Muscular Dystrophy: Current Clinical Signals and Hypotheses for Accelerated Progress

David Aphkhazava; Khatuna Saganelidze; Nino Gamtkitsulashvili; Levan Gulua; Mzia Tsiklauri; Manana Makharadze; Nodar Sulashvili; Sonali Senthilnathan; Aneesa Saleem; Cezar Goletiani; Nino Nebieridze; Lolita Shengelia; George Maglakelidze; Ilia Atanelishvili

Authors

David Aphkhazava PhD, Professor, East West University, Tbilisi, Georgia. Orcid: https://orcid.org/0000- 0001- 6216-64
Khatuna Saganelidze MD, PhD, Professor, Vice-President International Accreditation/Authorization Expert in Higher Education, East-West University, Tbilisi, Georgia
Nino Gamtkitsulashvili Researcher, East-West University, 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, Tbilis, 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 of «Research Retrieval and Academic Letters» (April 2-3, 2026). Warsaw, Poland 427 Dentistry and Pharmacy at Tbilisi Humanitarian Teaching University; Tbilisi, Georgia; Orcid: https://orcid.org/0000-0002-9005-8577.
Sonali Senthilnathan East West University, Tbilisi, Georgia
Aneesa Saleem East West University, Tbilisi, Georgia
Cezar Goletiani Professor at Free University of Tbilisi, Tbilisi, Georgia, Head scientist at Agricultural University of Georgia, Tbilisi, Georgia
Nino Nebieridze Associate Professor at Free University of Tbilisi, Tbilisi, Georgia
Lolita Shengelia PhD, Invited lecturer of Georgian National University, Tbilisi, Georgia; Invited lecturer of Georgian American 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, DMD, gene therapy, micro-dystrophin, AAV, immunogenicity, liver toxicity, myocarditis, early intervention, combination therapy, gene editing, therapeutic durability

Abstract

Gene therapy for Duchenne muscular dystrophy (DMD) has entered a clinically transformative yet still transitional phase. Current adeno-associated virus (AAV) micro-dystrophin approaches have demonstrated biologic activity and encouraging functional signals in treated patients, including favorable effects on timed motor outcomes and evidence of durable benefit in longer-term follow-up analyses; however, short-term randomized data have also shown that the primary functional endpoint was not consistently met at 52 weeks, indicating that clinical benefit remains heterogeneous and incompletely captured by existing trial designs. At the same time, safety remains a major constraint, with acute serious liver injury, myocarditis, thrombocytopenia, infusion-related reactions, and immune-mediated myositis underscoring the narrow therapeutic window of systemic high-dose AAV delivery. On the basis of current evidence, four hypotheses may explain how substantial progress could be achieved: first, earlier intervention—ideally before extensive fibrosis and loss of muscle regenerative capacity—may produce larger and more durable clinical effects; second, immune-tailored strategies, including pre-treatment immune profiling, tolerogenic protocols, and vector/transgene designs that reduce immunogenicity, may improve persistence of expression and safety; third, combination approaches pairing gene replacement with anti-inflammatory, anti-fibrotic, or pro-regenerative therapies may convert partial molecular rescue into stronger functional benefit; and fourth, next-generation platforms—such as improved muscle/cardiac tropic vectors, redosing-enabled systems, fuller dystrophin restoration, or precise gene editing—may overcome current payload and durability limitations. Together, available data suggest that meaningful progress in DMD will likely come not from gene transfer alone, but from earlier, safer, and biologically integrated therapeutic strategies

Gene Therapy Outcomes in Duchenne Muscular Dystrophy: Current Clinical Signals and Hypotheses for Accelerated Progress

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