AAV9-mediated gene transfer of desmin ameliorates cardiomyopathy in desmin-deficient mice

• Published in: Gene therapy 2016-08, Vol.23 (8-9), p.673-679
• Main Authors: Heckmann, M B, Bauer, R, Jungmann, A, Winter, L, Rapti, K, Strucksberg, K-H, Clemen, C S, Li, Z, Schröder, R, Katus, H A, Müller, O J
• Format: Article
• Language: English
• Subjects: 14/19; 14/63; 42/44; 45/22; 45/41; 631/1647/2300/1514; 631/45/612/1228; 631/61/201; 64/110; 64/60; 692/699/75; 82/80; 96; Actin Cytoskeleton - metabolism; Animals; Biomedical and Life Sciences; Biomedicine; Cardiomyopathies - genetics; Cardiomyopathies - therapy; Cardiomyopathy; Care and treatment; Cell Biology; Dependovirus - genetics; Dependoviruses; Desmin - genetics; Desmin - metabolism; Gene Expression; Gene mutations; Gene Therapy; Genetic aspects; Genetic Therapy; Genetic Vectors - genetics; Heart diseases; Human Genetics; Intermediate Filament Proteins - metabolism; Life Sciences; Male; Mice; Mice, Inbred C57BL; Muscle Proteins - metabolism; Myocardial Contraction; Myocytes, Cardiac - metabolism; Nanotechnology; Original; original-article; Physiological aspects; Risk factors; Rodents; Ventricular Function, Left
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/gt.2016.40

Mutations of the human desmin ( DES ) gene cause autosomal dominant and recessive myopathies affecting skeletal and cardiac muscle tissue. Desmin knockout mice (DES-KO), which develop progressive myopathy and cardiomyopathy, mirror rare human recessive desminopathies in which mutations on both DES alleles lead to a complete ablation of desmin protein expression. Here, we investigated whether an adeno-associated virus-mediated gene transfer of wild-type desmin cDNA (AAV-DES) attenuates cardiomyopathy in these mice. Our approach leads to a partial reconstitution of desmin protein expression and the de novo formation of the extrasarcomeric desmin–syncoilin network in cardiomyocytes of treated animals. This finding was accompanied by reduced fibrosis and heart weights and improved systolic left-ventricular function when compared with control vector-treated DES-KO mice. Since the re-expression of desmin protein in cardiomyocytes of DES-KO mice restores the extrasarcomeric desmin–syncoilin cytoskeleton, attenuates the degree of cardiac hypertrophy and fibrosis, and improves contractile function, AAV-mediated desmin gene transfer may be a novel and promising therapeutic approach for patients with cardiomyopathy due to the complete lack of desmin protein expression.