Successful compensation for dystrophin deficiency by a helper-dependent adenovirus expressing full-length utrophin

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DOIResolve DOI: http://doi.org/10.1038/sj.mt.6300260
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TypeArticle
Journal titleMolecular Therapy
Volume15
Issue10
Pages17671774; # of pages: 8
SubjectAnimal; animals; bio; deficiency; dna; dystrophin; mice; muscles; phenotype; protein; proteins; therapy
AbstractHelper-dependent adenovirus vector (AdV)–mediated full-length dystrophin expression leads to significant mitigation of the dystrophic phenotype of the mdx mouse. However, dystrophin, as a neoantigen, elicits antibody formation. As an alternative approach, we evaluated gene transfer of full-length murine utrophin, a functional homologue of dystrophin that is normally present only at the neuromuscular junction. A single injection in the tibialis anterior (TA) muscle of the helper-dependent adenovirus vector encoding utrophin provided very good transduction, with 58% of fibers demonstrating sarcolemmal utrophin expression in the neonates, and 35% utrophin-positive (Utr⁺) fibers in adults. The presence of utrophin prevented extensive necrosis in the neonates, halted further necrosis in the adults, and led to restoration of sarcolemmal expression of dystrophin-associated proteins up to 1 year after injection. Marked physiological improvement was observed in both neonates and adults. Neither increased humoral responses nor cellular immune responses were evident. However, there was a time-related decline of the initial high utrophin expression. Although viral DNA persisted in animals that were injected in the neonatal stage, viral DNA levels decreased in muscles of adult mice. These results demonstrate that although utrophin gene transfer leads to amelioration of the dystrophic phenotype, the effects are not sustained upon loss of utrophin expression.
Publication date
LanguageEnglish
AffiliationNRC Biotechnology Research Institute; National Research Council Canada
Peer reviewedNo
NRC number47807
47807
NPARC number3539215
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Record identifier1110fc54-5b38-46cd-8d2a-9526ed4cd5d3
Record created2009-03-01
Record modified2016-05-09
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