{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T20:42:17Z","timestamp":1789764137134,"version":"4.0.1"},"reference-count":34,"publisher":"SAGE Publications","issue":"7-8","license":[{"start":{"date-parts":[[2021,4,1]],"date-time":"2021-04-01T00:00:00Z","timestamp":1617235200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2021,4,1]],"date-time":"2021-04-01T00:00:00Z","timestamp":1617235200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Human Gene Therapy"],"published-print":{"date-parts":[[2021,4]]},"abstract":"<jats:p>\n                    Limb-girdle muscular dystrophy type 2D\/R3 (LGMD2D\/R3) is a progressive muscular dystrophy that manifests with muscle weakness, respiratory abnormalities, and in rare cases cardiomyopathy. LGMD2D\/R3 is caused by mutations in the SGCA gene resulting in loss of protein and concomitant loss of some or all components of the dystrophin-associated glycoprotein complex. The sgca-null (\n                    <jats:italic toggle=\"yes\">\n                      sgca\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    ) mouse recapitulates the clinical phenotype of patients with LGMD2D\/R3, including dystrophic features such as muscle necrosis and fibrosis, elevated serum creatine kinase (CK), and reduction in the generation of absolute muscle force and locomotor activity. Thus,\n                    <jats:italic toggle=\"yes\">\n                      sgca\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    mice provide a relevant model to test the safety and efficacy of gene transfer. We designed a self-complementary AAVrh74 vector containing a codon-optimized full-length human SGCA (hSGCA) transgene driven by a muscle-specific promoter, shortened muscle creatine kinase (tMCK). In this report, we test the efficacy and safety of\n                    <jats:uri xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/scAAVrh74.tMCK.hSGCA\">scAAVrh74.tMCK.hSGCA<\/jats:uri>\n                    in\n                    <jats:italic toggle=\"yes\">\n                      sgca\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    mice using a dose-escalation design to evaluate a single systemic injection of 1.0\u2009\u00d7\u200910\n                    <jats:sup>12<\/jats:sup>\n                    , 3.0\u2009\u00d7\u200910\n                    <jats:sup>12<\/jats:sup>\n                    , and 6.0\u2009\u00d7\u200910\n                    <jats:sup>12<\/jats:sup>\n                    vg total dose compared with vehicle-treatment and wild-type mice. In\n                    <jats:italic toggle=\"yes\">\n                      sgca\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    mice, treatment with\n                    <jats:uri xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/scAAVrh74.tMCK.hSGCA\">scAAVrh74.tMCK.hSGCA<\/jats:uri>\n                    resulted in robust expression of \u03b1-sarcoglycan protein at the sarcolemma membrane in skeletal muscle at all doses tested. In addition,\n                    <jats:uri xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/scAAVrh74.tMCK.hSGCA\">scAAVrh74.tMCK.hSGCA<\/jats:uri>\n                    was effective in improving the histopathology of limb and diaphragm muscle of\n                    <jats:italic toggle=\"yes\">\n                      sgca\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    mice, as indicated by reductions in fibrosis, central nucleation, and normalization of myofiber size. These molecular changes were concomitant with significant increases in specific force generation in the diaphragm and tibialis anterior muscle, protection against eccentric force loss, and reduction in serum CK. Locomotor activity was improved at all doses of vector-treated compared with vehicle-treated\n                    <jats:italic toggle=\"yes\">\n                      sgca\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    mice. Lastly, vector toxicity was not detected in a serum chemistry panel and by gross necropsy. Collectively, these findings provide support for a systemic delivery of\n                    <jats:uri xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/scAAVrh74.tMCK.hSGCA\">scAAVrh74.tMCK.hSGCA<\/jats:uri>\n                    in a clinical setting for the treatment of LGMD2D\/R3.\n                  <\/jats:p>","DOI":"10.1089\/hum.2019.199","type":"journal-article","created":{"date-parts":[[2020,12,22]],"date-time":"2020-12-22T01:23:13Z","timestamp":1608600193000},"page":"390-404","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":23,"title":["Preclinical Systemic Delivery of Adeno-Associated \u03b1-Sarcoglycan Gene Transfer for Limb-Girdle Muscular Dystrophy"],"prefix":"10.1177","volume":"32","author":[{"given":"Danielle A.","family":"Griffin","sequence":"first","affiliation":[{"name":"Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA"},{"name":"Sarepta Therapeutics, Inc., Cambridge, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric R.","family":"Pozsgai","sequence":"additional","affiliation":[{"name":"Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA"},{"name":"Sarepta Therapeutics, Inc., Cambridge, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristin N.","family":"Heller","sequence":"additional","affiliation":[{"name":"Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachael A.","family":"Potter","sequence":"additional","affiliation":[{"name":"Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA"},{"name":"Sarepta Therapeutics, Inc., Cambridge, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellyn L.","family":"Peterson","sequence":"additional","affiliation":[{"name":"Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA"},{"name":"Sarepta Therapeutics, Inc., Cambridge, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise R.","family":"Rodino-Klapac","sequence":"additional","affiliation":[{"name":"Sarepta Therapeutics, Inc., Cambridge, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2021,4,19]]},"reference":[{"key":"e_1_3_6_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/mus.26077"},{"key":"e_1_3_6_3_2","doi-asserted-by":"publisher","DOI":"10.3233\/JND-150105"},{"key":"e_1_3_6_4_2","unstructured":"McNally EM. The Sarcoglycans. In: Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000\u20132013. Accessed June22 2020. 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Isometric and eccentric force generation assessment of skeletal muscles isolated from murine models of muscular dystrophies. J Vis Exp, 2031; 71:e50036.","journal-title":"J Vis Exp"},{"key":"e_1_3_6_26_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.111.031716"},{"key":"e_1_3_6_27_2","doi-asserted-by":"publisher","DOI":"10.1089\/10430349950018427"},{"key":"e_1_3_6_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2009.254"},{"key":"e_1_3_6_29_2","first-page":"1","article-title":"Respiratory insufficiency as a presenting symptom of LGMD2D in adulthood","volume":"23","author":"Walter MC","year":"2004","unstructured":"Walter MC, , Dekomien G, , Schlotter-Weigel B, et al. Respiratory insufficiency as a presenting symptom of LGMD2D in adulthood. 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