AAV9-mediated gene transfer of desmin ameliorates cardiomyopathy in desmin-deficient mice.
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.
Department of Internal Medicine III, University Hospital Heidelberg, Heidelberg, Germany.|DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany.
M B
MB
Heckmann
Department of Internal Medicine III, University Hospital Heidelberg, Heidelberg, Germany.
R
R
Bauer
Department of Internal Medicine III, University Hospital Heidelberg, Heidelberg, Germany.
A
A
Jungmann
Institute of Neuropathology, University Hospital Erlangen, Erlangen, Germany.
L
L
Winter
Department of Internal Medicine III, University Hospital Heidelberg, Heidelberg, Germany.|DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany.
K
K
Rapti
Institute of Neuropathology, University Hospital Erlangen, Erlangen, Germany.
K-H
KH
Strucksberg
Institute of Biochemistry I, Medical Faculty, University of Cologne, Cologne, Germany.
C S
CS
Clemen
Institut de Biologie Paris Seine, Université Pierre et Marie Curie, Paris, France.
Z
Z
Li
Institute of Neuropathology, University Hospital Erlangen, Erlangen, Germany.
R
R
Schröder
Department of Internal Medicine III, University Hospital Heidelberg, Heidelberg, Germany.|DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany.
H A
HA
Katus
Department of Internal Medicine III, University Hospital Heidelberg, Heidelberg, Germany.|DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany.
O J
OJ
Müller
D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics / Q000628:therapy*; D000229:Dependovirus / Q000235:genetics*; D003893:Desmin / Q000235:genetics* / Q000378:metabolism; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D007381:Intermediate Filament Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009124:Muscle Proteins / Q000378:metabolism; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism; D016277:Ventricular Function, Left
D003893:Desmin; D007381:Intermediate Filament Proteins; D009124:Muscle Proteins; C503782:Sync protein, mouse