4.5 Article

Viral vector producing antisense RNA restores myotonic dystrophy myoblast functions

Journal

GENE THERAPY
Volume 10, Issue 9, Pages 795-802

Publisher

NATURE PUBLISHING GROUP
DOI: 10.1038/sj.gt.3301955

Keywords

myotonic dystrophy; myoblast; gene therapy

Funding

  1. NIAMS NIH HHS [AR01D44387] Funding Source: Medline
  2. NIA NIH HHS [AG16392] Funding Source: Medline

Ask authors/readers for more resources

Myotonic dystrophy (DM1) is caused by the expansion of a trinucleotide repeat (CTG) located in the 3' untranslated region of the myotonic dystrophy protein kinase gene, for which currently there is no effective treatment. The data available suggest that misregulation of RNA homeostasis may play a major role in DM1 muscle pathogenesis. This indicates that the specific targeting of the mutant DMPK transcripts is essential to raise the rationale basis for the development of a specific gene therapy for DM1. We have produced a retrovirus which expresses a 149-bp antisense RNA complementary to the (CUG) 13 repeats and to the 110-bp region following the repeats sequence to increase the specificity. This construct was introduced into human DM1 myoblasts, resulting in a preferential decrease in mutant DMPK transcripts, and effective restoration of human DM1 myoblast functions such as myoblast fusion and the uptake of glucose. It was previously shown that delay of muscle differentiation and insulin resistance in DM1 are associated with misregulation of CUGBP1 protein levels. The analysis of CUGBP1 levels and activity in DM1 cells expressing the antisense RNA indicated a correction of CUGBP1 expression in infected DM1 cells. We therefore show that current antisense RNA delivered in vitro using a retrovirus is not only capable of inhibiting mutant DMPK transcripts, but also can ameliorate dystrophic muscle pathology at the cellular levels.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.5
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available