{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T04:35:00Z","timestamp":1791434100205,"version":"4.3.3"},"reference-count":46,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2017,5,12]]},"abstract":"<jats:sec>\n            <jats:title>\n              <jats:underline>Rationale:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>Targeted genetic engineering using programmable nucleases such as transcription activator\u2013like effector nucleases (TALENs) is a valuable tool for precise, site-specific genetic modification in the human genome.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Objective:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>The emergence of novel technologies such as human induced pluripotent stem cells (iPSCs) and nuclease-mediated genome editing represent a unique opportunity for studying cardiovascular diseases in vitro.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Methods and Results:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>\n              By incorporating extensive literature and database searches, we designed a collection of TALEN constructs to knockout 88 human genes that are associated with cardiomyopathies and congenital heart diseases. The TALEN pairs were designed to induce double-strand DNA break near the starting codon of each gene that either disrupted the start codon or introduced a frameshift mutation in the early coding region, ensuring faithful gene knockout. We observed that all the constructs were active and disrupted the target locus at high frequencies. To illustrate the utility of the TALEN\u2013mediated knockout technique, 6 individual genes (\n              <jats:italic>TNNT2, LMNA\/C, TBX5, MYH7, ANKRD1<\/jats:italic>\n              , and\n              <jats:italic>NKX2.5<\/jats:italic>\n              ) were knocked out with high efficiency and specificity in human iPSCs. By selectively targeting a pathogenic mutation (\n              <jats:italic>TNNT2 p.R173W<\/jats:italic>\n              ) in patient-specific iPSC-derived cardiac myocytes, we demonstrated that the knockout strategy ameliorates the dilated cardiomyopathy phenotype in vitro. In addition, we modeled the Holt\u2013Oram syndrome in iPSC-cardiac myocytes in vitro and uncovered novel pathways regulated by\n              <jats:italic>TBX5<\/jats:italic>\n              in human cardiac myocyte development.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Conclusions:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>Collectively, our study illustrates the powerful combination of iPSCs and genome editing technologies for understanding the biological function of genes, and the pathological significance of genetic variants in human cardiovascular diseases. The methods, strategies, constructs, and iPSC lines developed in this study provide a validated, readily available resource for cardiovascular research.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.116.309948","type":"journal-article","created":{"date-parts":[[2017,3,1]],"date-time":"2017-03-01T02:10:18Z","timestamp":1488334218000},"page":"1561-1571","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":64,"title":["A Comprehensive TALEN-Based Knockout Library for Generating Human-Induced Pluripotent Stem Cell\u2013Based Models for Cardiovascular Diseases"],"prefix":"10.1161","volume":"120","author":[{"given":"Ioannis","family":"Karakikes","sequence":"first","affiliation":[{"name":"From the Stanford Cardiovascular Institute (I.K., V.T., J.L., S.D., I.I., M.A., R.S., H.W., N.M., N.-Y.S., T.S., N.W., K.D.W., E.M., J.C.W.), Department of Cardiothoracic Surgery (I.K.), Division of Cardiovascular Medicine, Department of Medicine (V.T., J.C.W.), CA; Institute of Stem Cell Biology and Regenerative Medicine (D.A.C., V.S., J.C.W.), Departments of Pediatrics (A.H., M.H.P.), Pathology (K.D.W.), and Obstetrics and Gynecology (V.S.), Stanford University School of Medicine, CA; Berlin..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vittavat","family":"Termglinchan","sequence":"additional","affiliation":[{"name":"From the Stanford Cardiovascular Institute (I.K., V.T., J.L., S.D., I.I., M.A., R.S., H.W., N.M., N.-Y.S., T.S., N.W., K.D.W., E.M., J.C.W.), Department of Cardiothoracic Surgery (I.K.), Division of Cardiovascular Medicine, Department of Medicine (V.T., J.C.W.), CA; Institute of Stem Cell Biology and Regenerative Medicine (D.A.C., V.S., J.C.W.), Departments of Pediatrics (A.H., M.H.P.), Pathology (K.D.W.), and Obstetrics and Gynecology (V.S.), Stanford University School of Medicine, CA; Berlin..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana A.","family":"Cepeda","sequence":"additional","affiliation":[{"name":"From the Stanford Cardiovascular Institute (I.K., V.T., J.L., S.D., I.I., M.A., R.S., H.W., N.M., N.-Y.S., T.S., N.W., K.D.W., E.M., J.C.W.), Department of Cardiothoracic Surgery (I.K.), Division of Cardiovascular Medicine, Department of Medicine (V.T., J.C.W.), CA; Institute of Stem Cell Biology and Regenerative Medicine (D.A.C., V.S., J.C.W.), Departments of Pediatrics (A.H., M.H.P.), Pathology (K.D.W.), and Obstetrics and Gynecology (V.S.), Stanford University School of Medicine, CA; Berlin..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaecheol","family":"Lee","sequence":"additional","affiliation":[{"name":"From the Stanford Cardiovascular Institute (I.K., V.T., J.L., S.D., I.I., M.A., R.S., H.W., N.M., N.-Y.S., T.S., N.W., K.D.W., E.M., J.C.W.), Department of Cardiothoracic Surgery (I.K.), Division of Cardiovascular Medicine, Department of Medicine (V.T., J.C.W.), CA; Institute of Stem Cell 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the Stanford Cardiovascular Institute (I.K., V.T., J.L., S.D., I.I., M.A., R.S., H.W., N.M., N.-Y.S., T.S., N.W., K.D.W., E.M., J.C.W.), Department of Cardiothoracic Surgery (I.K.), Division of Cardiovascular Medicine, Department of Medicine (V.T., J.C.W.), CA; Institute of Stem Cell Biology and Regenerative Medicine (D.A.C., V.S., J.C.W.), Departments of Pediatrics (A.H., M.H.P.), Pathology (K.D.W.), and Obstetrics and Gynecology (V.S.), Stanford University School of Medicine, CA; Berlin..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilanit","family":"Itzhaki","sequence":"additional","affiliation":[{"name":"From the Stanford Cardiovascular Institute (I.K., V.T., J.L., S.D., I.I., M.A., R.S., H.W., N.M., N.-Y.S., T.S., N.W., K.D.W., E.M., J.C.W.), Department of Cardiothoracic Surgery (I.K.), Division of Cardiovascular Medicine, Department of Medicine (V.T., J.C.W.), CA; Institute of Stem Cell Biology and Regenerative Medicine (D.A.C., V.S., J.C.W.), Departments of 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