SERCA2a overexpression improves muscle function in a canine Duchenne muscular dystrophy model.

Autor:	Kodippili K; Department of Molecular Microbiology and Immunology, School of Medicine, The University of Missouri, Columbia, MO 65212, USA., Hakim CH; Department of Molecular Microbiology and Immunology, School of Medicine, The University of Missouri, Columbia, MO 65212, USA., Burke MJ; Department of Molecular Microbiology and Immunology, School of Medicine, The University of Missouri, Columbia, MO 65212, USA., Yue Y; Department of Molecular Microbiology and Immunology, School of Medicine, The University of Missouri, Columbia, MO 65212, USA., Teixeira JA; Department of Molecular Microbiology and Immunology, School of Medicine, The University of Missouri, Columbia, MO 65212, USA., Zhang K; Department of Molecular Microbiology and Immunology, School of Medicine, The University of Missouri, Columbia, MO 65212, USA., Yao G; Department of Chemical and Biomedical Engineering, College of Engineering, The University of Missouri, Columbia, MO 65212, USA., Babu GJ; Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, NJ 07103, USA., Herzog RW; Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, IN 46202, USA., Duan D; Department of Molecular Microbiology and Immunology, School of Medicine, The University of Missouri, Columbia, MO 65212, USA.; Department of Chemical and Biomedical Engineering, College of Engineering, The University of Missouri, Columbia, MO 65212, USA.; Department of Neurology, School of Medicine, The University of Missouri, Columbia, MO 65212, USA.; Department of Biomedical Sciences, College of Veterinary Medicine, The University of Missouri, Columbia, MO 65212, USA.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Methods & clinical development [Mol Ther Methods Clin Dev] 2024 May 20; Vol. 32 (2), pp. 101268. Date of Electronic Publication: 2024 May 20 (Print Publication: 2024).
DOI:	10.1016/j.omtm.2024.101268
Abstrakt:	Excessive cytosolic calcium accumulation contributes to muscle degeneration in Duchenne muscular dystrophy (DMD). Sarco/endoplasmic reticulum calcium ATPase (SERCA) is a sarcoplasmic reticulum (SR) calcium pump that actively transports calcium from the cytosol into the SR. We previously showed that adeno-associated virus (AAV)-mediated SERCA2a therapy reduced cytosolic calcium overload and improved muscle and heart function in the murine DMD model. Here, we tested whether AAV SERCA2a therapy could ameliorate muscle disease in the canine DMD model. 7.83 × 10 13 vector genome particles of the AAV vector were injected into the extensor carpi ulnaris (ECU) muscles of four juvenile affected dogs. Contralateral ECU muscles received excipient. Three months later, we observed widespread transgene expression and significantly increased SERCA2a levels in the AAV-injected muscles. Treatment improved SR calcium uptake, significantly reduced calpain activity, significantly improved contractile kinetics, and significantly enhanced resistance to eccentric contraction-induced force loss. Nonetheless, muscle histology was not improved. To evaluate the safety of AAV SERCA2a therapy, we delivered the vector to the ECU muscle of adult normal dogs. We achieved strong transgene expression without altering muscle histology and function. Our results suggest that AAV SERCA2a therapy has the potential to improve muscle performance in a dystrophic large mammal. Competing Interests: D.D. is a member of the scientific advisory board for Solid Biosciences and an equity holder of Solid Biosciences. D.D. is a member of the scientific advisory board for Sardocor Corp. D.D. is an inventor of several issued and filed patents on AAV vector and DMD gene therapy. The Duan lab has received research support unrelated to this project from Elenae Therapeutics and Satellos Bioscience in the last 3 years. R.W.H. is serving on scientific advisory boards for the Regeneron Pharmaceuticals-Intellia Therapeutics collaboration, Prevail Therapeutics, Pfizer, and Biomarin and is also receiving funding from Roche. (© 2024 The Author(s).)
Databáze:	MEDLINE
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