دورية أكاديمية
Efficacy and muscle safety assessment of fukutin-related protein gene therapy
| العنوان: | Efficacy and muscle safety assessment of fukutin-related protein gene therapy |
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| المؤلفون: | Halli Benasutti, Joseph W. Maricelli, Jane Seto, John Hall, Christine Halbert, Jacqueline Wicki, Lydia Heusgen, Nicholas Purvis, Michael Regnier, David C. Lin, Buel D. Rodgers, Jeffrey S. Chamberlain |
| المصدر: | Molecular Therapy: Methods & Clinical Development, Vol 30, Iss , Pp 65-80 (2023) |
| بيانات النشر: | Elsevier |
| سنة النشر: | 2023 |
| المجموعة: | Directory of Open Access Journals: DOAJ Articles |
| مصطلحات موضوعية: | gene therapy, fukutin-related protein, FKRP, limb-girdle muscular dystrophy type R9 (LGMDR9), adeno-associated viral vector (AAV), physiology, Genetics, QH426-470, Cytology, QH573-671 |
| الوصف: | Limb-girdle muscular dystrophy type R9 (LGMDR9) is a muscle-wasting disease that begins in the hip and shoulder regions of the body. This disease is caused by mutations in fukutin-related protein (FKRP), a glycosyltransferase critical for maintaining muscle cell integrity. Here we investigated potential gene therapies for LGMDR9 containing an FKRP expression construct with untranslated region (UTR) modifications. Initial studies treated an aged dystrophic mouse model (FKRPP448L) with adeno-associated virus vector serotype 6 (AAV6). Grip strength improved in a dose- and time-dependent manner, injected mice exhibited fewer central nuclei and serum creatine kinase levels were 3- and 5-fold lower compared to those in non-injected FKRPP448L mice. Treatment also partially stabilized the respiratory pattern during exercise and improved treadmill running, partially protecting muscle from exercise-induced damage. Western blotting of C2C12 myotubes using a novel rabbit antibody confirmed heightened translation with the UTR modifications. We further explored the question of FKRP toxicity in wild-type mice using high doses of two additional muscle-tropic capsids: AAV9 and AAVMYO1. No toxic effects were detected with either therapeutic agent. These data further support the feasibility of gene therapy to treat LGMDR9. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 2329-0501 |
| العلاقة: | http://www.sciencedirect.com/science/article/pii/S2329050123000840Test; https://doaj.org/toc/2329-0501Test; https://doaj.org/article/a9db696fcc7143e8a0480dc385b78ddfTest |
| DOI: | 10.1016/j.omtm.2023.05.022 |
| الإتاحة: | https://doi.org/10.1016/j.omtm.2023.05.022Test https://doaj.org/article/a9db696fcc7143e8a0480dc385b78ddfTest |
| رقم الانضمام: | edsbas.83E034BD |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 23290501 |
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| DOI: | 10.1016/j.omtm.2023.05.022 |