Academic Journal
Microutrophin expression in dystrophic mice displays myofiber type differences in therapeutic effects
| العنوان: | Microutrophin expression in dystrophic mice displays myofiber type differences in therapeutic effects |
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| المؤلفون: | Banks, Glen B., Chamberlain, Jeffrey S., Odom, Guy L. |
| المساهمون: | Cox, Gregory A., National Institutes of Health, National Institute of Neurological Disorders and Stroke, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Muscular Dystrophy Association |
| المصدر: | PLOS Genetics ; volume 16, issue 11, page e1009179 ; ISSN 1553-7404 |
| بيانات النشر: | Public Library of Science (PLoS) |
| سنة النشر: | 2020 |
| المجموعة: | PLOS Publications (via CrossRef) |
| الوصف: | Gene therapy approaches for DMD using recombinant adeno-associated viral (rAAV) vectors to deliver miniaturized (or micro) dystrophin genes to striated muscles have shown significant progress. However, concerns remain about the potential for immune responses against dystrophin in some patients. Utrophin, a developmental paralogue of dystrophin, may provide a viable treatment option. Here we examine the functional capacity of an rAAV-mediated microutrophin (μUtrn) therapy in the mdx 4cv mouse model of DMD. We found that rAAV-μUtrn led to improvement in dystrophic histopathology & mostly restored the architecture of the neuromuscular and myotendinous junctions. Physiological studies of tibialis anterior muscles indicated peak force maintenance, with partial improvement of specific force. A fundamental question for μUtrn therapeutics is not only can it replace critical functions of dystrophin, but whether full-length utrophin impacts the therapeutic efficacy of the smaller, highly expressed μUtrn. As such, we found that μUtrn significantly reduced the spacing of the costameric lattice relative to full-length utrophin. Further, immunostaining suggested the improvement in dystrophic pathophysiology was largely influenced by favored correction of fast 2b fibers. However, unlike μUtrn, μdystrophin (μDys) expression did not show this fiber type preference. Interestingly, μUtrn was better able to protect 2a and 2d fibers in mdx :utrn -/- mice than in mdx 4cv mice where the endogenous full-length utrophin was most prevalent. Altogether, these data are consistent with the role of steric hindrance between full-length utrophin & μUtrn within the sarcolemma. Understanding the stoichiometry of this effect may be important for predicting clinical efficacy. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1371/journal.pgen.1009179 |
| الاتاحة: | http://dx.doi.org/10.1371/journal.pgen.1009179 https://dx.plos.org/10.1371/journal.pgen.1009179 |
| Rights: | https://creativecommons.org/publicdomain/zero/1.0/ |
| رقم الانضمام: | edsbas.6E4E9321 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1371/journal.pgen.1009179 |
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