{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T23:14:10Z","timestamp":1780614850782,"version":"3.54.1"},"reference-count":31,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2024,9,26]],"date-time":"2024-09-26T00:00:00Z","timestamp":1727308800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100001982","name":"BSF","doi-asserted-by":"publisher","award":["2021191"],"award-info":[{"award-number":["2021191"]}],"id":[{"id":"10.13039\/100001982","id-type":"DOI","asserted-by":"publisher"}]},{"name":"ARC","award":["2021191"],"award-info":[{"award-number":["2021191"]}]},{"name":"Research authority, Sheba medical center","award":["2021191"],"award-info":[{"award-number":["2021191"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Severe protein C deficiency (SPCD) is a rare inherited thrombotic disease associated with high morbidity and mortality. In the current study, we established a viable murine model of SPCD, enabling preclinical gene therapy studies. By creating SPCD mice with severe hemophilia A (PROC\u2212\/\u2212\/F8\u2212), the multi-month survival of SPCD mice enabled the exploration of recombinant adeno-associated viral vector-PC (rAAV8-PC) gene therapy (GT). rAAV8- PC (1012 vg\/kg of AAV8-PC) was injected via the tail vein into 6\u20138-week-old PROC\u2212\/\u2212\/F8- mice. Their plasma PC antigen levels (median of 714 ng\/mL, range 166\u20132488 ng\/mL) and activity (303.5 \u00b1 59%) significantly increased to the normal range after GT compared to untreated control animals. PC\u2019s presence in the liver after GT was also confirmed by immunofluorescence staining. Our translational research results provide the first proof of concept that an infusion of rAAV8-PC increases PC antigen and activity in mice and may contribute to future GT in SPCD. Further basic research of SPCD mice with prolonged survival due to the rebalancing of this disorder using severe hemophilia A may provide essential data regarding PC\u2019s contribution to specific tissues\u2019 development, local PC generation, and its regulation in inflammatory conditions.<\/jats:p>","DOI":"10.3390\/ijms251910336","type":"journal-article","created":{"date-parts":[[2024,9,26]],"date-time":"2024-09-26T04:05:46Z","timestamp":1727323546000},"page":"10336","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["A Novel Murine Model Enabling rAAV8-PC Gene Therapy for Severe Protein C Deficiency"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3971-0336","authenticated-orcid":false,"given":"Sarina","family":"Levy-Mendelovich","sequence":"first","affiliation":[{"name":"National Hemophilia Center, Thrombosis & Hemostasis Institute, Sheba Medical Center, Ramat Gan 52621, Israel"},{"name":"Amalia Biron Research Institute of Thrombosis & Hemostasis, Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv 6997801, Israel"},{"name":"Talpiot Medical Leadership Program, Sheba Medical Center, Ramat Gan 52621, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6920-790X","authenticated-orcid":false,"given":"Einat","family":"Avishai","sequence":"additional","affiliation":[{"name":"National Hemophilia Center, Thrombosis & Hemostasis Institute, Sheba Medical Center, Ramat Gan 52621, Israel"},{"name":"Amalia Biron Research Institute of Thrombosis & Hemostasis, Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6772-4140","authenticated-orcid":false,"given":"Benjamin J.","family":"Samelson-Jones","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"Division of Hematology, Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rima","family":"Dardik","sequence":"additional","affiliation":[{"name":"National Hemophilia Center, Thrombosis & Hemostasis Institute, Sheba Medical Center, Ramat Gan 52621, Israel"},{"name":"Amalia Biron Research Institute of Thrombosis & Hemostasis, Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-8651-2501","authenticated-orcid":false,"given":"Tami","family":"Brutman-Barazani","sequence":"additional","affiliation":[{"name":"National Hemophilia Center, Thrombosis & Hemostasis Institute, Sheba Medical Center, Ramat Gan 52621, Israel"},{"name":"Amalia Biron Research Institute of Thrombosis & Hemostasis, Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yael","family":"Nisgav","sequence":"additional","affiliation":[{"name":"National Hemophilia Center, Thrombosis & Hemostasis Institute, Sheba Medical Center, Ramat Gan 52621, Israel"},{"name":"Amalia Biron Research Institute of Thrombosis & Hemostasis, Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1279-2557","authenticated-orcid":false,"given":"Tami","family":"Livnat","sequence":"additional","affiliation":[{"name":"National Hemophilia Center, Thrombosis & Hemostasis Institute, Sheba Medical Center, Ramat Gan 52621, Israel"},{"name":"Amalia Biron Research Institute of Thrombosis & Hemostasis, Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3494-9823","authenticated-orcid":false,"given":"Gili","family":"Kenet","sequence":"additional","affiliation":[{"name":"National Hemophilia Center, Thrombosis & Hemostasis Institute, Sheba Medical Center, Ramat Gan 52621, Israel"},{"name":"Amalia Biron Research Institute of Thrombosis & Hemostasis, Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1111\/jth.12247","article-title":"Mechanisms of anticoagulant and cytoprotective actions of the protein C pathway","volume":"11","author":"Bouwens","year":"2013","journal-title":"J. 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