{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T21:53:59Z","timestamp":1792101239760,"version":"4.4.0"},"reference-count":75,"publisher":"SAGE Publications","issue":"19-20","license":[{"start":{"date-parts":[[2021,10,1]],"date-time":"2021-10-01T00:00:00Z","timestamp":1633046400000},"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":[[2021,10]]},"abstract":"<jats:p>\n                    Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare disease caused by recessive mutations in the\n                    <jats:italic toggle=\"yes\">TYMP<\/jats:italic>\n                    gene, which encodes the enzyme thymidine phosphorylase (TP). In this study, the efficient integration of a\n                    <jats:italic toggle=\"yes\">TYMP<\/jats:italic>\n                    transgene into introns of the\n                    <jats:italic toggle=\"yes\">Tymp<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">Alb<\/jats:italic>\n                    loci of hepatocytes in a murine model of MNGIE was achieved by the coordinated delivery and activity of CRISPR\/Cas9 and a\n                    <jats:italic toggle=\"yes\">TYMP<\/jats:italic>\n                    cDNA. CRISPR\/Cas9 was delivered either as mRNA using lipid nanoparticle (LNP) or polymeric nanoparticle, respectively, or in an AAV2\/8 viral vector; the latter was also used to package the\n                    <jats:italic toggle=\"yes\">TYMP<\/jats:italic>\n                    cDNA. Insertion of the cDNA template downstream of the\n                    <jats:italic toggle=\"yes\">Tymp<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">Alb<\/jats:italic>\n                    promoters ensured transgene expression. The best\n                    <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                    results were obtained using LNP carrying the CRISPR\/Cas9 mRNAs. Treated mice showed a consistent long-term (1 year) reduction in plasma nucleoside (thymidine and deoxyuridine) levels that correlated with the presence of\n                    <jats:italic toggle=\"yes\">TYMP<\/jats:italic>\n                    mRNA and functional enzyme in liver cells. In mice with an edited\n                    <jats:italic toggle=\"yes\">Alb<\/jats:italic>\n                    locus, the transgene produced a hybrid Alb-hTP protein that was secreted, with supraphysiological levels of TP activity detected in the plasma. Equivalent results were obtained in mice edited at the\n                    <jats:italic toggle=\"yes\">Tymp<\/jats:italic>\n                    locus. Finally, some degree of gene editing was found in animals treated only with AAV vectors containing the DNA templates, in the absence of nucleases, although there was no impact on plasma nucleoside levels. Overall, these results demonstrate the feasibility of liver-directed genome editing in the long-term correction of MNGIE, with several advantages over other methods.\n                  <\/jats:p>","DOI":"10.1089\/hum.2021.152","type":"journal-article","created":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T10:14:05Z","timestamp":1631182445000},"page":"1210-1223","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":19,"title":["Preclinical Assessment of a Gene-Editing Approach in a Mouse Model of Mitochondrial Neurogastrointestinal Encephalomyopathy"],"prefix":"10.1177","volume":"32","author":[{"given":"Marta","family":"Par\u00e9s","sequence":"first","affiliation":[{"name":"Gene and Cell Therapy, Institut de Recerca Hospital Universitari Vall d'Hebron (VHIR), Universitat Aut\u00f2noma de Barcelona (UAB), Barcelona, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Fornaguera","sequence":"additional","affiliation":[{"name":"Grup d'Enginyeria de Materials (GEMAT), Institut Qu\u00edmic de Sarri\u00e0 (IQS), Ramon Llull University (URL), Barcelona, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ferran","family":"Vila-Juli\u00e0","sequence":"additional","affiliation":[{"name":"Research Group on Neuromuscular and Mitochondrial Diseases, Institut de Recerca Hospital Universitari Vall d'Hebron (VHIR), Universitat Aut\u00f2noma de Barcelona (UAB), and Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sejin","family":"Oh","sequence":"additional","affiliation":[{"name":"Grup d'Enginyeria de Materials (GEMAT), Institut Qu\u00edmic de Sarri\u00e0 (IQS), Ramon Llull University (URL), Barcelona, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven H.Y.","family":"Fan","sequence":"additional","affiliation":[{"name":"Acuitas Therapeutics, Vancouver, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying K.","family":"Tam","sequence":"additional","affiliation":[{"name":"Acuitas Therapeutics, Vancouver, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Comes","sequence":"additional","affiliation":[{"name":"Blood and Tissue Bank, Barcelona, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco","family":"Vidal","sequence":"additional","affiliation":[{"name":"Blood and Tissue Bank, Barcelona, Spain."},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramon","family":"Mart\u00ed","sequence":"additional","affiliation":[{"name":"Research Group on Neuromuscular and Mitochondrial Diseases, Institut de Recerca Hospital Universitari Vall d'Hebron (VHIR), Universitat Aut\u00f2noma de Barcelona (UAB), and Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvador","family":"Borr\u00f3s","sequence":"additional","affiliation":[{"name":"Grup d'Enginyeria de Materials (GEMAT), Institut Qu\u00edmic de Sarri\u00e0 (IQS), Ramon Llull University (URL), Barcelona, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1677-9851","authenticated-orcid":false,"given":"Jordi","family":"Barquinero","sequence":"additional","affiliation":[{"name":"Gene and Cell Therapy, Institut de Recerca Hospital Universitari 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