{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T23:31:26Z","timestamp":1780615886268,"version":"3.54.1"},"reference-count":55,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"12","license":[{"start":{"date-parts":[[2024,12,1]],"date-time":"2024-12-01T00:00:00Z","timestamp":1733011200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2024,12]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      PC (protein C) is a plasma anticoagulant encoded by\n                      <jats:italic toggle=\"yes\">PROC<\/jats:italic>\n                      ; mutation in both\n                      <jats:italic toggle=\"yes\">PROC<\/jats:italic>\n                      alleles results in neonatal purpura fulminans\u2014a fatal systemic thrombotic disorder. In the present study, we aimed to develop a genome editing treatment to cure congenital PC deficiency.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>We generated an engineered APC (activated PC) to insert a furin-cleaving peptide sequence between light and heavy chains. The engineered PC was expressed in the liver of mice using an adeno-associated virus vector or CRISPR\/Cas9 (clustered regularly interspaced short palindromic repeats\/clustered regularly interspaced short palindromic repeat\u2013associated 9)-mediated genome editing using an adeno-associated virus vector in vivo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      The engineered PC could be released in its activated form and significantly prolonged the plasma coagulation time independent of the cofactor activity of PS (protein S) in vitro. The adeno-associated virus vector-mediated expression of the engineered PC, but not wild-type PC, prolonged coagulation time owing to the inhibition of activated coagulation FV (factor V) in a dose-dependent manner and abolished pathological thrombus formation in vivo in C57BL\/6J mice. The insertion of\n                      <jats:italic toggle=\"yes\">EGFP<\/jats:italic>\n                      (enhanced green fluorescent protein) sequence conjugated with self-cleaving peptide sequence at\n                      <jats:italic toggle=\"yes\">Alb<\/jats:italic>\n                      locus via neonatal in vivo genome editing using adeno-associated virus vector resulted in the expression of EGFP in 7% of liver cells, mainly via homology-directed repair, in mice. Finally, we succeeded in improving the survival of PC-deficient mice by expressing the engineered PC via neonatal genome editing in vivo.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>These results suggest that the expression of engineered PC via neonatal genome editing is a potential cure for severe congenital PC deficiency.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/atvbaha.123.319460","type":"journal-article","created":{"date-parts":[[2024,11,7]],"date-time":"2024-11-07T05:00:39Z","timestamp":1730955639000},"page":"2616-2627","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":4,"title":["Cure of Congenital Purpura Fulminans via Expression of Engineered Protein C Through Neonatal Genome Editing in Mice"],"prefix":"10.1161","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2600-657X","authenticated-orcid":true,"given":"Tomoki","family":"Togashi","sequence":"first","affiliation":[{"name":"Department of Clinical Laboratory Science, Division of Health Sciences, Graduate School of Medical Science, Kanazawa University, Ishikawa, Japan (T.T., E.M.)."},{"name":"Department of Biochemistry, Jichi Medical University School of Medicine, Tochigi, Japan (T.T., N.B., Y.K., M.H., T.H., T.O.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3004-8457","authenticated-orcid":true,"given":"Nemekhbayar","family":"Baatartsogt","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Jichi Medical University School of Medicine, Tochigi, Japan (T.T., N.B., Y.K., M.H., T.H., 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