Real-world outcomes of delandistrogene moxeparvovec gene therapy: Motor outcomes and emerging safety concerns

Dennis J Keselman¹, Juliana C Small², Tiffany Seneviratne², Sarah McCague², Taylor L Kaschak³, Sabrina W Yum¹, Andrea O'Brien³, John F Brandsema¹, Tamir Diamond⁴, Kathleen M Loomes⁴, Kimberly Y Lin⁵, Carol A Wittlieb-Weber⁵, Oscar H Mayer⁶, Scott G Daniel⁷, Amy T Waldman⁸, Benjamin J Samelson-Jones⁹, Susan E Matesanz¹⁰, Lindsey A George¹¹

Affiliations

¹ Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
² Clinical In Vivo Gene Therapy, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
³ Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁴ Bioinformatics and Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
⁵ Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Cardiology, Cardiac Center, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁶ Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Pulmonology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁷ Bioinformatics and Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁸ Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Clinical In Vivo Gene Therapy, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁹ Clinical In Vivo Gene Therapy, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
¹⁰ Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Clinical In Vivo Gene Therapy, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. Electronic address: matesanzs@chop.edu.
¹¹ Clinical In Vivo Gene Therapy, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. Electronic address: georgel@chop.edu.

PMID: 41047627
DOI: 10.1016/j.ymthe.2025.10.007

Free article

Real-world outcomes of delandistrogene moxeparvovec gene therapy: Motor outcomes and emerging safety concerns

Dennis J Keselman et al. Mol Ther. 2025.

Free article

. 2025 Oct 4:S1525-0016(25)00828-7.

doi: 10.1016/j.ymthe.2025.10.007. Online ahead of print.

Authors

Affiliations

¹ Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
² Clinical In Vivo Gene Therapy, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
³ Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁴ Bioinformatics and Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
⁵ Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Cardiology, Cardiac Center, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁶ Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Pulmonology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁷ Bioinformatics and Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁸ Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Clinical In Vivo Gene Therapy, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁹ Clinical In Vivo Gene Therapy, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
¹⁰ Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Clinical In Vivo Gene Therapy, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. Electronic address: matesanzs@chop.edu.
¹¹ Clinical In Vivo Gene Therapy, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. Electronic address: georgel@chop.edu.

PMID: 41047627
DOI: 10.1016/j.ymthe.2025.10.007

Abstract

Delandistrogene moxeparvovec is currently the only commercially approved gene therapy for Duchenne muscular dystrophy (DMD). Herein, we report real-world data of 11 ambulatory patients with DMD, ages 4-6, treated with commercial delandistrogene moxeparvovec. Patients were prospectively and uniformly monitored for 1 year post-gene transfer for safety and motor outcomes. Nine patients experienced 15 treatment-related toxicities, and 4 required escalation of corticosteroids. Side effects included gastrointestinal symptoms (n = 7), liver enzyme abnormalities (n = 4), acute liver injury (n = 2), and troponin I elevations (n = 3). In both patients with acute liver injury, troponin I elevations occurred in close temporal association beginning 8-9 weeks post-gene transfer and were responsive to corticosteroids. The clinical courses of these two patients were at least partially consistent with a cellular immune response to the adeno-associated viral vector (AAV) capsid. Troponin I elevations were asymptomatic and without acute functional changes on echocardiogram. The cohort had improvements in year 1 motor function assessments relative to baseline, including a statistically significant median 4-point increase in North Star Ambulatory Assessment score; however, important confounding factors, e.g., baseline corticosteroid use, limit interpretation and will be important to control for in future real-world datasets. Additional follow-up is required to determine long-term safety and motor outcomes, with unclear generalizability of our results.

Keywords: AAV; DMD; delandistrogene moxeparvovec; real-world outcomes.

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Conflict of interest statement

Declaration of interests A.T.W. has received research support from Sarepta Therapeutics and Pfizer. J.F.B. has served as a consultant for AveXis/Novartis, Biogen, Dyne Therapeutics, Edgewise Therapeutics, FibroGen, Genentech, Momenta/Janssen, NS Pharma, Pfizer, PTC Therapeutics, Sarepta Therapeutics, Scholar Rock Holding Corp, and Takeda and as a site investigator for research studies for Alexion Pharmaceuticals, Astellas, AveXis/Novartis, Biogen, Biohaven, Dyne Therapeutics, FibroGen, Genentech, ML Bio Solutions, Pfizer, PTC Therapeutics, Sarepta Therapeutics, and Scholar Rock Holding Corp. S.E.M. has served on advisory boards for Sarepta Therapeutics and has received research support from Sarepta Therapeutics, Dyne Therapeutics, Pfizer, and Genentech/Roche. C.A.W.-W. has served on an advisory board for Sarepta Therapeutics. L.A.G. is on the scientific advisory board of Form Bio, is a consultant for CSL Behring and Pfizer, and received licensing fees from Spark Therapeutics/F. Hoffman-La Roche AG.

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Real-world outcomes of delandistrogene moxeparvovec gene therapy: Motor outcomes and emerging safety concerns

Affiliations

Real-world outcomes of delandistrogene moxeparvovec gene therapy: Motor outcomes and emerging safety concerns

Authors

Affiliations

Abstract

Conflict of interest statement

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