AAV-mediated cardiac gene transfer of wild-type desmin in mouse models for recessive desminopathies
Ruppert T, Heckmann MB, Rapti K, Schultheis D, Jungmann A, Katus HA, Winter L, Frey N, Clemen CS, Schröder R, Müller OJ (2020)
Publication Type: Journal article
Publication year: 2020
Journal
DOI: 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 × 1012 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.
Authors with CRIS profile
Involved external institutions
Germany (DE)How to cite
APA:
Ruppert, T., Heckmann, M.B., Rapti, K., Schultheis, D., Jungmann, A., Katus, H.A.,... Müller, O.J. (2020). AAV-mediated cardiac gene transfer of wild-type desmin in mouse models for recessive desminopathies. Gene Therapy. https://doi.org/10.1038/s41434-020-0147-7
MLA:
Ruppert, T., et al. "AAV-mediated cardiac gene transfer of wild-type desmin in mouse models for recessive desminopathies." Gene Therapy (2020).
BibTeX: Download