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

Par Conseil national de recherches du Canada

DOI	Trouver le DOI : https://doi.org/10.1038/sj.mt.6300260
Auteur	Rechercher : Deol, Jatinderpal R.; Rechercher : Danialou, Gawiyou; Rechercher : Larochelle, Nancy; Rechercher : Bourget, Mylène; Rechercher : Moon, Joon-Shik; Rechercher : Liu, An-Bang; Rechercher : Gilbert, Rénald¹; Rechercher : Petrof, Basil J.; Rechercher : Nalbantoglu, Josephine; Rechercher : Karpati, George
Affiliation	Conseil national de recherches du Canada. Institut de recherche en biotechnologie du CNRC
Format	Texte, Article
Sujet	biotechnology; deficiency; DNA; dystrophin; mice; muscles; phenotype; protein; proteins; therapy
Résumé	Helper-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.
Date de publication	2007-07-31
Dans	Molecular Therapy 15, nº 10 (31 juillet 2007) : 1767–1774.
Langue	anglais
Numéro du CNRC	47807 NRCC 47807
Numéro NPARC	3539215
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Identificateur de l’enregistrement	1110fc54-5b38-46cd-8d2a-9526ed4cd5d3
Enregistrement créé	2009-03-01
Enregistrement modifié	2020-05-10

Date de modification :: 2024-12-21