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AAV-mediated cardiac gene transfer of wild-type desmin in mouse models for recessive desminopathies

Ruppert, T. and Heckmann, M.B. and Rapti, K. and Schultheis, D. and Jungmann, A. and Katus, H. A. and Winter, L. and Frey, N. and Clemen, C.S. and Schröder, R. and Müller, O. (2020) AAV-mediated cardiac gene transfer of wild-type desmin in mouse models for recessive desminopathies. Gene Therapy, Epub ahead of print. Springer Nature. doi: 10.1038/s41434-020-0147-7. ISSN 0969-7128.

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Official URL: https://www.nature.com/articles/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 wildtype 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 wildtype 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

Item URL in elib:https://elib.dlr.de/135970/
Document Type:Article
Title:AAV-mediated cardiac gene transfer of wild-type desmin in mouse models for recessive desminopathies
Authors:
AuthorsInstitution or Email of AuthorsAuthor's ORCID iD
Ruppert, T.Department of Internal Medicine III, University of Kiel, Kiel, GermanyUNSPECIFIED
Heckmann, M.B.UNSPECIFIEDhttps://orcid.org/0000-0002-3085-1282
Rapti, K.Internal Medicine III, University Hospital Heidelberg, Heidelberg, GermanyUNSPECIFIED
Schultheis, D.Institute of Neuropathology, University Hospital ErlangenUNSPECIFIED
Jungmann, A.Internal Medicine III, University Hospital Heidelberg, Heidelberg, GermanyUNSPECIFIED
Katus, H. A.Internal Medicine III, University Hospital Heidelberg, Heidelberg, GermanyUNSPECIFIED
Winter, L.Institute of Neuropathology, University Hospital ErlangenUNSPECIFIED
Frey, N.Department of Internal Medicine III, University of Kiel, Kiel, GermanyUNSPECIFIED
Clemen, C.S.Institute of Aerospace Medicine, German Aerospace Center (DLR), 51147 Cologne, Germanyhttps://orcid.org/0000-0002-1291-4219
Schröder, R.Institute of Neuropathology, University Hospital ErlangenUNSPECIFIED
Müller, O.Department of Internal Medicine III, University of Kiel, Kiel, Germanyhttps://orcid.org/0000-0001-8223-2638
Date:22 April 2020
Journal or Publication Title:Gene Therapy
Refereed publication:Yes
Open Access:Yes
Gold Open Access:No
In SCOPUS:Yes
In ISI Web of Science:Yes
DOI :10.1038/s41434-020-0147-7
Page Range:Epub ahead of print
Publisher:Springer Nature
ISSN:0969-7128
Status:Published
Keywords:AAV-mediated, recessive desminopathies
HGF - Research field:Aeronautics, Space and Transport
HGF - Program:Space
HGF - Program Themes:Research under Space Conditions
DLR - Research area:Raumfahrt
DLR - Program:R FR - Research under Space Conditions
DLR - Research theme (Project):R - Vorhaben Systemphysiologie (old)
Location: Köln-Porz
Institutes and Institutions:Institute of Aerospace Medicine > Muscle and Bone Metabolism
Deposited By: Arndt, Carina
Deposited On:10 Sep 2020 12:28
Last Modified:30 Sep 2020 10:22

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