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

dc.contributor.authorKodippili, Kasun
dc.contributor.authorHakim, Chady H.
dc.contributor.authorBurke, Matthew J.
dc.contributor.authorYue, Yongping
dc.contributor.authorTeixeira, James A.
dc.contributor.authorZhang, Keqing
dc.contributor.authorYao, Gang
dc.contributor.authorBabu, Gopal J.
dc.contributor.authorHerzog, Roland W.
dc.contributor.authorDuan, Dongsheng
dc.contributor.departmentPediatrics, School of Medicine
dc.date.accessioned2024-08-27T10:53:19Z
dc.date.available2024-08-27T10:53:19Z
dc.date.issued2024-05-20
dc.description.abstractExcessive 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 × 1013 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.
dc.eprint.versionFinal published version
dc.identifier.citationKodippili K, Hakim CH, Burke MJ, et al. SERCA2a overexpression improves muscle function in a canine Duchenne muscular dystrophy model. Mol Ther Methods Clin Dev. 2024;32(2):101268. Published 2024 May 20. doi:10.1016/j.omtm.2024.101268
dc.identifier.urihttps://hdl.handle.net/1805/42972
dc.language.isoen_US
dc.publisherElsevier
dc.relation.isversionof10.1016/j.omtm.2024.101268
dc.relation.journalMolecular Therapy: Methods & Clinical Development
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 Internationalen
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0
dc.sourcePMC
dc.subjectDuchenne muscular dystrophy
dc.subjectDMD
dc.subjectSERCA2a
dc.subjectAAV
dc.subjectCanine model
dc.subjectMuscle function
dc.subjectTreg
dc.subjectTyrosine mutant AAV9
dc.subjectSarcoplasmic reticulum
dc.subjectExtensor carpi ulnaris
dc.titleSERCA2a overexpression improves muscle function in a canine Duchenne muscular dystrophy model
dc.typeArticle
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