{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T04:15:43Z","timestamp":1791346543632,"version":"4.3.1"},"reference-count":60,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"22","license":[{"start":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T00:00:00Z","timestamp":1638230400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2021,11,30]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>Loss of dystrophin protein causes Duchenne muscular dystrophy (DMD), characterized by progressive degeneration of cardiac and skeletal muscles, and mortality in adolescence or young adulthood. Although cardiac failure has risen as the leading cause of mortality in patients with DMD, effective therapeutic interventions remain underdeveloped, in part, because of the lack of a suitable preclinical model.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>\n              We analyzed a novel murine model of DMD created by introducing a 4-bp deletion into exon 4, one of the exons encoding the actin-binding domain 1 of dystrophin (referred to as\n              <jats:italic>Dmd<\/jats:italic>\n              <jats:sup>E4*<\/jats:sup>\n              mice). Echocardiography, microcomputed tomography, muscle force measurement, and histological analysis were performed to determine cardiac and skeletal muscle defects in these mice. Using this model, we examined the feasibility of using a cytidine base editor to install exon skipping and rescue dystrophic cardiomyopathy in vivo. AAV9-based CRISPR\/Cas9-AID (eTAM) together with AAV9-sgRNA was injected into neonatal\n              <jats:italic>Dmd<\/jats:italic>\n              <jats:sup>E4*<\/jats:sup>\n              mice, which were analyzed 2 or 12 months after treatment to evaluate the extent of exon skipping, dystrophin restoration, and phenotypic improvements of cardiac and skeletal muscles.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              <jats:italic>Dmd<\/jats:italic>\n              <jats:sup>E4*<\/jats:sup>\n              mice recapitulated many aspects of human DMD, including shortened life span (by \u224850%), progressive cardiomyopathy, kyphosis, profound loss of muscle strength, and myocyte degeneration. A single-dose administration of AAV9-eTAM instituted &gt;50% targeted exon skipping in the\n              <jats:italic>Dmd<\/jats:italic>\n              transcripts and restored up to 90% dystrophin in the heart. As a result, early ventricular remodeling was prevented and cardiac and skeletal muscle functions were improved, leading to an increased life span of the\n              <jats:italic>Dmd<\/jats:italic>\n              <jats:sup>E4*<\/jats:sup>\n              mice. Despite gradual decline of AAV vector and base editor expression, dystrophin restoration and pathophysiological rescue of muscular dystrophy were long lasted for at least 1 year.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>Our study demonstrates the feasibility and efficacy to institute exon skipping through an enhanced TAM (eTAM) for therapeutic application(s).<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.121.054628","type":"journal-article","created":{"date-parts":[[2021,10,26]],"date-time":"2021-10-26T15:41:58Z","timestamp":1635262918000},"page":"1760-1776","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":51,"title":["Therapeutic Exon Skipping Through a CRISPR-Guided Cytidine Deaminase Rescues Dystrophic Cardiomyopathy in Vivo"],"prefix":"10.1161","volume":"144","author":[{"given":"Jia","family":"Li","sequence":"first","affiliation":[{"name":"Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China (J.L., K.W., Y.Z., T.Q., L.Z., H.Q., X.C.)."},{"name":"Chinese Academy of Sciences, China. Joint Research Center of Hangzhou First Hospital Group and Westlake University, Zhejiang, China (J.L., K.W., Y.Z., T.Q., X.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaiying","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China (J.L., K.W., Y.Z., T.Q., L.Z., H.Q., X.C.)."},{"name":"Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China (J.L., K.W., Y.Z., T.Q., L.Z., H.Q., X.C.)."},{"name":"Chinese Academy of Sciences, China. Joint Research Center of Hangzhou First Hospital Group and Westlake University, Zhejiang, China (J.L., K.W., Y.Z., T.Q., X.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9622-2692","authenticated-orcid":true,"given":"Yuchen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China (J.L., K.W., Y.Z., T.Q., L.Z., H.Q., X.C.)."},{"name":"Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China (J.L., K.W., Y.Z., T.Q., L.Z., H.Q., X.C.)."},{"name":"Chinese Academy of Sciences, China. Joint Research Center of Hangzhou First Hospital Group and Westlake University, Zhejiang, China (J.L., K.W., Y.Z., T.Q., X.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuan","family":"Qi","sequence":"additional","affiliation":[{"name":"Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China (J.L., K.W., Y.Z., T.Q., L.Z., H.Q., X.C.)."},{"name":"Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China (J.L., K.W., Y.Z., T.Q., L.Z., H.Q., X.C.)."},{"name":"Shanghai Jiao Tong University School of Medicine (SJTUSM), China (T.Q.)."},{"name":"Chinese Academy of Sciences, China. Joint Research Center of Hangzhou First Hospital Group and Westlake University, Zhejiang, China (J.L., K.W., Y.Z., T.Q., X.C.)."},{"name":"Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China (J.L., K.W., Y.Z., T.Q., L.Z., H.Q., X.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juanjuan","family":"Yuan","sequence":"additional","affiliation":[{"name":"Shunde Hospital, Southern Medical University (The First People\u2019s Hospital of Shunde), Foshan City, Guangdong Province, China (J.Y., H.Q.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China (J.L., K.W., Y.Z., T.Q., L.Z., H.Q., X.C.)."},{"name":"Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China (J.L., K.W., Y.Z., T.Q., L.Z., H.Q., X.C.)."},{"name":"Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China (J.L., K.W., Y.Z., T.Q., L.Z., H.Q., X.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Qiu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China (J.L., K.W., Y.Z., T.Q., L.Z., H.Q., X.C.)."},{"name":"Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China (J.L., K.W., Y.Z., T.Q., L.Z., H.Q., X.C.)."},{"name":"Shunde Hospital, Southern Medical University (The First People\u2019s Hospital of Shunde), Foshan City, Guangdong Province, China (J.Y., H.Q.)."},{"name":"CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences (H.Q., J.W., H.-T.Y.)"},{"name":"Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China (J.L., K.W., Y.Z., T.Q., L.Z., H.Q., X.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinxi","family":"Wang","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Tissue Microenvironment and Tumor, Laboratory of Molecular Cardiology, Shanghai Institute of Nutrition and Health (J.W., H.-T.Y.)"},{"name":"CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences (H.Q., J.W., H.-T.Y.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6297-9037","authenticated-orcid":true,"given":"Huang-Tian","family":"Yang","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Tissue Microenvironment and Tumor, Laboratory of Molecular Cardiology, Shanghai Institute of Nutrition and Health (J.W., H.-T.Y.)"},{"name":"CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences (H.Q., J.W., H.-T.Y.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China (Y.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla (Y.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5072-9225","authenticated-orcid":true,"given":"Xing","family":"Chang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China (J.L., K.W., Y.Z., T.Q., L.Z., H.Q., X.C.)."},{"name":"Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China (J.L., K.W., Y.Z., T.Q., L.Z., H.Q., X.C.)."},{"name":"Chinese Academy of Sciences, China. 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