| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
From the Center for Gene Therapy (L.R.R.-K., K.R.C., J.R.M.), The Research Institute at Nationwide Children's Hospital, Departments of Pediatrics and Neurology, Ohio State University; and the Harvard Gene Therapy Initiative (J.-S.L., R.C.M.), Department of Genetics, Harvard Medical School.
* To whom correspondence should be addressed. E-mail: Jerry.Mendell{at}NationwideChildrens.org.
Background: Alpha-sarcoglycan (
-SG) deficiency (limb-girdle muscular dystrophy [LGMD] type 2D) is the most common form of sarcoglycan-LGMD. No treatment is currently available. Prior studies suggest that overexpression of -SG via adeno-associated virus (AAV)-mediated gene transfer results in poorly sustained gene expression related to transgene toxicity. These findings potentially preclude gene therapy as a treatment approach for LGMD2D.
Methods: The human -SG gene (h-SG) was directly transferred to the tibialis anterior muscle of 4- to 5-week-old -SG KO mice using AAV, type 1. The gene was placed under control of either the ubiquitously expressed cytomegalovirus (CMV) promoter or muscle specific promoters that included desmin, muscle creatine kinase (MCK), and its further modification, truncated MCK (tMCK). Low (3 x 109 vg) and high (3 x 1010 vg) doses of AAV1.h-SG were administered.
Results: Sustained gene expression was observed irrespective of promoters at 6 and 12 weeks post gene transfer. Quantitation of -SG gene expression by fiber counts yielded similar levels of myofiber transduction for both MCK promoters (60 to 70%), while 34% of fibers were transduced with the DES promoter. There was a trend toward lower expression at the 12-week time point with the CMV promoter. Western blot analysis revealed -SG overexpression using CMV and both the MCK promoters.
Conclusion: Our data demonstrate robust and sustained adeno-associated virus type 1 alpha-sarcoglycan gene expression under control of muscle creatine kinase promoters, without evidence of cytotoxicity. These findings support the use of gene therapy as a potential treatment approach for limb-girdle muscular dystrophy type 2D.
This article has been cited by other articles:
|
|
 |
|
  A Y Manzur and F Muntoni Diagnosis and new treatments in muscular dystrophies Postgrad. Med. J., November 1, 2009; 85(1009): 622 - 630. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A Y Manzur and F Muntoni Diagnosis and new treatments in muscular dystrophies J. Neurol. Neurosurg. Psychiatry, July 1, 2009; 80(7): 706 - 714. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. W. Kaspar, C. E. Wills, and B. K. Kaspar Gene Therapy and Informed Consent Decision Making: Nursing Research Directions Biol Res Nurs, July 1, 2009; 11(1): 98 - 107. [Abstract] [PDF]
|
|
|
|
 |
|
 R. Xu, S. DeVries, M. Camboni, and P. T. Martin Overexpression of Galgt2 Reduces Dystrophic Pathology in the Skeletal Muscles of Alpha Sarcoglycan-Deficient Mice Am. J. Pathol., July 1, 2009; 175(1): 235 - 247. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Li, C. Long, Y. Yue, and D. Duan Sub-physiological sarcoglycan expression contributes to compensatory muscle protection in mdx mice Hum. Mol. Genet., April 1, 2009; 18(7): 1209 - 1220. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. J. Muller and H. Lochmuller Sarcoglycans take center stage in gene transfer therapy Neurology, July 22, 2008; 71(4): 234 - 235. [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
