Various effects of AAV9-mediated βARKct gene therapy on the heart in dystrophin-deficient (mdx) mice and δ-sarcoglycan-deficient (Sgcd-/-) mice.

Abstract

So far effective strategies to treat cardiomyopathy in patients with muscular dystrophies are still not clearly defined. Previously, treatment with β-blockers showed beneficial effects on the development of cardiomyopathy in dystrophin-deficient (mdx) mice, but not in δ-sarcoglycan-deficient (Sgcd-/-) mice. We therefore aimed to study a more specific approach to target maladaptive β-adrenergic signalling in these mice. It has been shown that lowering cardiac G-protein-coupled-receptor-kinase-2 (GRK2) activity with βARKct expression, a peptide inhibitor of protein-coupled-receptor-kinase-2 (GRK2), results in improvement of heart failure in several different animal models. We therefore investigated whether adeno-associated virus type 9 (AAV9)-mediated gene delivery of βARKct, could ameliorate cardiac pathology in mdx and Sgcd-/- mice. We found that long-term treatment with AAV9- βARKct-cDNA with a cardiac-specific promoter significantly improves left ventricular systolic function and reduces myocardial hypertrophy in mdx mice, whereas only mild beneficial effects on cardiac function is observed in Sgcd-/- mice. Interestingly, in contrast to mdx mice neither GRK2 nor nuclear-factor-kappaB (NFκB) were upregulated in Sgcd-/- mice. Taken together, effectiveness of AAV-mediated βARKct therapy may vary between different genetic mutations and presumably depend on the state of adrenergic dysregulation mediated through the upregulation of GRK2.

• Authors: Ralf Bauer, Helene Enns, Andreas Jungmann, Barbara Leuchs, Christian Volz, Stefanie Schinkel, Walter J Koch, Philip W Raake, Patrick Most, Hugo A Katus, Oliver J Müller
• Journal: Neuromuscular disorders : NMD (Neuromuscul Disord) Vol. 29 Issue 3 Pg. 231-241 (03 2019) ISSN: 1873-2364 [Electronic] England
• PMID: 30782477 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018. Published by Elsevier B.V.

Chemical References

• Dystrophin
• Sarcoglycans
• Sgcd protein, mouse

Topics

• Animals
• Cardiomyopathies (genetics)
• Dependovirus (genetics)
• Dystrophin (deficiency, genetics)
• Genetic Therapy (methods)
• Heart (physiopathology)
• Heart Failure (genetics, physiopathology)
• Mice, Inbred mdx
• Mice, Transgenic
• Muscular Dystrophies (genetics, metabolism)
• Sarcoglycans (genetics)
• Ventricular Function, Left (genetics)