AAV-mediated cardiac gene transfer of wild-type desmin in mouse models for recessive desminopathies
Open Access
- 1 November 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Gene Therapy
- Vol. 27 (10-11), 516-524
- https://doi.org/10.1038/s41434-020-0147-7
Abstract
Mutations in the human desmin gene cause autosomal-dominant and recessive cardiomyopathies and myopathies with marked phenotypic variability. Here, we investigated the effects of adeno-associated virus (AAV)-mediated cardiac wild-type desmin expression in homozygous desmin knockout (DKO) and homozygous R349P desmin knockin (DKI) mice. These mice serve as disease models for two subforms of autosomal-recessive desminopathies, the former for the one with a complete lack of desmin protein and the latter for the one with solely mutant desmin protein expression in conjunction with protein aggregation pathology in striated muscle. Two-month-old mice were injected with either a single dose of 5 x 10(12) AAV9-hTNT2-mDes (AAV-Des) vector genomes or NaCl as control. One week after injection, mice were subjected to a forced swimming exercise protocol for 4 weeks. Cardiac function was monitored over a period of 15 month after injection and before the mice were sacrificed for biochemical and morphological analysis. AAV-mediated cardiac expression of wild-type desmin in both the homozygous DKO and DKI backgrounds reached levels seen in wild-type mice. Notably, AAV-Des treated DKO mice showed a regular subcellular distribution of desmin as well as a normalization of functional and morphological cardiac parameters. Treated DKI mice, however, showed an aberrant subcellular localization of desmin, unchanged functional cardiac parameters, and a trend toward an increased cardiac fibrosis. In conclusion, the effect of a high-dose AAV9-based desmin gene therapy is highly beneficial for the heart in DKO animals, but not in DKI mice.This publication has 30 references indexed in Scilit:
- Recessive DES cardio/myopathy without myofibrillar aggregates: intronic splice variant silences one allele leaving only missense L190P-desminEuropean Journal of Human Genetics, 2019
- Molecular insights into cardiomyopathies associated with desmin (DES) mutationsBiophysical Reviews, 2018
- Neuromuscular endplate pathology in recessive desminopathiesNeurology, 2016
- Compound heterozygosity of predicted loss-of-function DESvariants in a family with recessive desminopathyBMC Medical Genetics, 2013
- A novel desmin mutation leading to autosomal recessive limb-girdle muscular dystrophy: distinct histopathological outcomes compared with desminopathiesJournal of Medical Genetics, 2013
- Recessive desmin-null muscular dystrophy with central nuclei and mitochondrial abnormalitiesActa Neuropathologica, 2013
- Desminopathies: pathology and mechanismsActa Neuropathologica, 2012
- Desmin-related myopathyClinical Genetics, 2010
- G.O.7 A homozygous desmin deletion causes an Emery-Dreifuss like recessive myopathy with desmin depletionNeuromuscular Disorders, 2009
- Restrictive Cardiomyopathy, Atrioventricular Block and Mild to Subclinical Myopathy in Patients With Desmin-Immunoreactive Material DepositsJournal of the American College of Cardiology, 1998