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Adeno\u2010associated virus (AAV) based gene therapy has improved dystrophin function, with sub\u2010optimal clinical outcomes. We reasoned that a combination of rational engineering of AAV9 capsids modified at the post\u2010translational modification sites, optimal promoter selection, and codon\u2010optimisation of the microdystrophin (\u03bcDys) can enhance the AAV9 vector functionality. Our initial promoter screening demonstrated improved dystrophin expression in muscle fibres with a ubiquitous CAG promoter (1.61\u2010fold in CAG vs. MHCK7,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.0001) in\n                    <jats:italic>mdx<\/jats:italic>\n                    mice. We then evaluated two engineered AAV9 capsids (N57Q, K51Q) containing CAG\u2010\u03bcDys intramuscularly in\u00a0vivo, which demonstrated a significant improvement in grip strength 18\u2009weeks after gene therapy. Subsequent evaluation of a codon\u2010optimised microdystrophin transgene under the control of the optimal CAG promoter and capsid (AAV9K51Q) by intramuscular administration revealed enhanced muscle grip strength and dystrophin\u2010glycoprotein complex restoration up to 4\u2009months after gene therapy. Based on the improved performance of AAV9K51Q vectors during intramuscular gene transfer, we performed a systemic administration of these vectors alone, and a comparison with the control group revealed a significantly increased muscle contraction force by 1.6\u20131.7 fold and a 30%\u201360% dystrophin restoration in skeletal and cardiac muscles, up to 14\u2009months after gene therapy. Collectively, our study underscores the therapeutic potential of engineered AAV9 vectors for potential clinical application in patients with DMD.\n                  <\/jats:p>","DOI":"10.1111\/jcmm.71078","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T03:20:03Z","timestamp":1773026403000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Bioengineered AAV9 and Optimised Microdystrophin Vectors Augment Phenotypic Rescue in a Murine Model of Duchenne Muscular Dystrophy"],"prefix":"10.1111","volume":"30","author":[{"given":"Mohankumar B.","family":"Senthilkumar","sequence":"first","affiliation":[{"name":"Department of Biological Sciences and Bioengineering and Mehta Family Center for Engineering in Medicine and Gangwal School of Medical Sciences and Technology Indian Institute of Technology  Kanpur Uttar Pradesh 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Sciences and Technology Indian Institute of Technology  Kanpur Uttar Pradesh India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pratiksha","family":"Sarangi","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences and Bioengineering and Mehta Family Center for Engineering in Medicine and Gangwal School of Medical Sciences and Technology Indian Institute of Technology  Kanpur Uttar Pradesh India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijayata","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences and Bioengineering and Mehta Family Center for Engineering in Medicine and Gangwal School of Medical Sciences and Technology Indian Institute of Technology  Kanpur Uttar Pradesh India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Narendra","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences and Bioengineering and Mehta Family Center for Engineering in Medicine and Gangwal School of Medical Sciences and Technology Indian Institute of Technology  Kanpur Uttar Pradesh India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Devyani","family":"Yenurkar","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering IIT (BHU)  Varanasi Uttar Pradesh India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3625-2272","authenticated-orcid":false,"given":"Sudip","family":"Mukherjee","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering IIT (BHU)  Varanasi Uttar Pradesh India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonal","family":"Amit","sequence":"additional","affiliation":[{"name":"Autonomous State Medical College  Kanpur Uttar Pradesh India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4997-3722","authenticated-orcid":false,"given":"Sameer","family":"Bhatia","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics and Genomics Sir Gangaram Hospital  New Delhi India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santosh K.","family":"Misra","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics and Genomics Sir Gangaram Hospital  New Delhi India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ratna Dua","family":"Puri","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics and Genomics Sir Gangaram Hospital  New Delhi India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Chamberlain","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Washington School of Medicine  Seattle Washington 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