PMID- 22248393
OWN - NLM
STAT- MEDLINE
DCOM- 20121203
LR  - 20120712
IS  - 1557-7422 (Electronic)
IS  - 1043-0342 (Linking)
VI  - 23
IP  - 6
DP  - 2012 Jun
TI  - Long-term preservation of cardiac structure and function after adeno-associated 
      virus serotype 9-mediated microdystrophin gene transfer in mdx mice.
PG  - 566-75
LID - 10.1089/hum.2011.017 [doi]
AB  - Dystrophin plays an important role in muscle contraction, linking the 
      intracellular cytoskeleton to the extracellular matrix. Mutations of the 
      dystrophin gene leading to a complete loss of the protein cause Duchenne muscular 
      dystrophy (DMD), frequently associated with severe cardiomyopathy. Early clinical 
      trials in DMD using gene transfer to skeletal muscle are underway, but gene 
      transfer to dystrophic cardiac muscle has not yet been tested in humans. The aim 
      of this study was to develop an optimized protocol for cardiac gene therapy in 
      the mouse model of dystrophin deficiency (mdx), using a cardiac promoter for 
      expression of a microdystrophin (muDys) transgene packaged into an 
      adeno-associated virus serotype 9 vector (AAV9). In this study adult mdx mice 
      were intravenously injected with 1x10(12) genomic particles of AAV9 vectors 
      carrying a cDNA encoding muDys under the control of either a ubiquitously active 
      cytomegalovirus (CMV) promoter or a cardiac-specific CMV-enhanced myosin light 
      chain (MLC0.26) promoter. After 10 months, both AAV9 vectors led to sustained 
      muDys expression in cardiac muscle, but the MLC promoter conferred about 4-fold 
      higher protein levels. AAV9-CMV-MLC0.26-muDys resulted in significant protection 
      of cardiac morphology and function as assessed by histopathology, 
      echocardiography, and left ventricular catheterization. In conclusion, we 
      established an AAV9-mediated gene transfer approach for efficient and specific 
      long-term muDys expression in the hearts of mdx mice, resulting in a sustained 
      therapeutic effect. Thus, this approach might be a basis for further translation 
      into a treatment strategy for DMD-associated cardiomyopathy.
FAU - Schinkel, Stefanie
AU  - Schinkel S
AD  - Department of Internal Medicine III, University of Heidelberg, 69120 Heidelberg, 
      Germany.
FAU - Bauer, Ralf
AU  - Bauer R
FAU - Bekeredjian, Raffi
AU  - Bekeredjian R
FAU - Stucka, Rolf
AU  - Stucka R
FAU - Rutschow, Desiree
AU  - Rutschow D
FAU - Lochmuller, Hanns
AU  - Lochmuller H
FAU - Kleinschmidt, Jurgen A
AU  - Kleinschmidt JA
FAU - Katus, Hugo A
AU  - Katus HA
FAU - Muller, Oliver J
AU  - Muller OJ
LA  - eng
GR  - G0601943/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120309
PL  - United States
TA  - Hum Gene Ther
JT  - Human gene therapy
JID - 9008950
RN  - 0 (Dystrophin)
SB  - IM
MH  - Animals
MH  - Blotting, Western
MH  - Dependovirus/*genetics
MH  - Disease Models, Animal
MH  - Dystrophin/*genetics/metabolism
MH  - *Genetic Therapy
MH  - Humans
MH  - Mice
MH  - Mice, Inbred mdx
MH  - Myocardium/*cytology/metabolism
MH  - Polymerase Chain Reaction
MH  - Promoter Regions, Genetic
EDAT- 2012/01/18 06:00
MHDA- 2012/12/10 06:00
CRDT- 2012/01/18 06:00
PHST- 2012/01/18 06:00 [entrez]
PHST- 2012/01/18 06:00 [pubmed]
PHST- 2012/12/10 06:00 [medline]
AID - 10.1089/hum.2011.017 [doi]
PST - ppublish
SO  - Hum Gene Ther. 2012 Jun;23(6):566-75. doi: 10.1089/hum.2011.017. Epub 2012 Mar 9.