Gene Therapy Rescues Cardiac Dysfunction in Duchenne Muscular Dystrophy Mice by Elevating Cardiomyocyte Deoxy-Adenosine Triphosphate

Stephen C Kolwicz Jr; John K Hall; Farid Moussavi-Harami; Xiolan Chen; Stephen D Hauschka; Jeffrey S Chamberlain; Michael Regnier; Guy L Odom

doi:10.1016/j.jacbts.2019.06.006

Gene Therapy Rescues Cardiac Dysfunction in Duchenne Muscular Dystrophy Mice by Elevating Cardiomyocyte Deoxy-Adenosine Triphosphate

JACC Basic Transl Sci. 2019 Oct 2;4(7):778-791. doi: 10.1016/j.jacbts.2019.06.006. eCollection 2019 Nov.

Authors

Stephen C Kolwicz Jr¹, John K Hall², Farid Moussavi-Harami³, Xiolan Chen^{4

5}, Stephen D Hauschka^{4

5}, Jeffrey S Chamberlain^{2

4

5}, Michael Regnier^{5

6

7}, Guy L Odom^{2

5

7}

Affiliations

¹ Mitochondria and Metabolism Center, University of Washington, Seattle, Washington.
² Department of Neurology, University of Washington, Seattle, Washington.
³ Division of Cardiology, Department of Medicine, University of Washington, Seattle, Washington.
⁴ Department of Biochemistry, University of Washington, Seattle, Washington.
⁵ Wellstone Muscular Dystrophy Specialized Research Center, University of Washington, Seattle, Washington.
⁶ Department of Bioengineering, University of Washington, Seattle, Washington.
⁷ Center for Cardiovascular Biology, University of Washington, Seattle, Washington.

Abstract

Mutations in the gene encoding for dystrophin leads to structural and functional deterioration of cardiomyocytes and is a hallmark of cardiomyopathy in Duchenne muscular dystrophy (DMD) patients. Administration of recombinant adeno-associated viral vectors delivering microdystrophin or ribonucleotide reductase (RNR), under muscle-specific regulatory control, rescues both baseline and high workload-challenged hearts in an aged, DMD mouse model. However, only RNR treatments improved both systolic and diastolic function under those conditions. Cardiac-specific recombinant adeno-associated viral treatment of RNR holds therapeutic promise for improvement of cardiomyopathy in DMD patients.

Keywords: CK8, miniaturized murine creatine kinase regulatory cassette; CMV, cytomegalovirus; DMD, Duchenne muscular dystrophy; RNR, ribonucleotide reductase; cTnT, cardiac troponin T; cardiomyopathy; dADP, deoxy-adenosine diphosphate; dATP, deoxy-adenosine triphosphate; diastolic dysfunction; dystrophin; mdx, mouse muscular dystrophy model; rAAV, recombinant adeno-associated viral vector; recombinant adeno-associated virus vectors; ribonucleotide reductase; μDys, microdystrophin.

Abstract

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