{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T16:52:54Z","timestamp":1781110374681,"version":"3.54.1"},"reference-count":30,"publisher":"National Academy of Sciences","issue":"23","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[1999,11,9]]},"abstract":"<jats:p>\n                    Development of\n                    <jats:italic>in utero<\/jats:italic>\n                    gene transfer approaches may provide therapies for genetic disorders with perinatal morbidity. In hemophilia A, prenatal and postnatal bleeding may be catastrophic, and modest increments in factor VIII (FVIII) activity are therapeutic. We performed transuterine i.p. gene transfer at day 15 of gestation in a murine model of hemophilia A. Normal, carrier (X\n                    <jats:sub>H<\/jats:sub>\n                    X), and FVIII-deficient (X\n                    <jats:sub>H<\/jats:sub>\n                    Y and X\n                    <jats:sub>H<\/jats:sub>\n                    X\n                    <jats:sub>H<\/jats:sub>\n                    ) fetuses injected with adenoviral vectors carrying luciferase or \u03b2-galactosidase reporter genes showed high-level gene expression with 91% fetal survival. The live-born rates of normal and FVIII-deficient animals injected\n                    <jats:italic>in utero<\/jats:italic>\n                    with adenovirus murine FVIII (3.3 \u00d7 10\n                    <jats:sup>5<\/jats:sup>\n                    plaque-forming units) was 87%. FVIII activity in plasma was 50.7 \u00b1 10.5% of normal levels at day 2 of life, 7.2 \u00b1 2.2% by day 15 of life, and no longer detectable at day 21 of life in hemophilic animals. Injection of higher doses of murine FVIII adenovirus at embryonic day 15 produced supranormal levels of FVIII activity in the neonatal period. PCR analysis identified viral genomes primarily in the liver, intestine, and spleen, although adenoviral DNA was detected in distal tissues when higher doses of adenovirus were administered. These studies show that transuterine i.p. injection of adenoviral vectors produces therapeutic levels of circulating FVIII throughout the neonatal period. The future development of efficient and persisting vectors that produce long-term gene expression may allow for\n                    <jats:italic>in utero<\/jats:italic>\n                    correction of genetic diseases originating in the fetal liver, hematopoietic stem cells, as well as other tissues.\n                  <\/jats:p>","DOI":"10.1073\/pnas.96.23.13324","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:40:52Z","timestamp":1027680052000},"page":"13324-13329","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":61,"title":["Short-term correction of factor VIII deficiency in a murine model of hemophilia A after delivery of adenovirus murine factor VIII\n                    <i>in utero<\/i>"],"prefix":"10.1073","volume":"96","author":[{"given":"G. S.","family":"Lipshutz","sequence":"first","affiliation":[{"name":"Departments of Surgery and Medicine, Third and Parnassus Avenues, University of California, San Francisco, CA 94143-0793; and Department of Genetics, Clinical Research Building, University of Pennsylvania, 415 Curie Boulevard, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R.","family":"Sarkar","sequence":"additional","affiliation":[{"name":"Departments of Surgery and Medicine, Third and Parnassus Avenues, University of California, San Francisco, CA 94143-0793; and Department of Genetics, Clinical Research Building, University of Pennsylvania, 415 Curie Boulevard, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L.","family":"Flebbe-Rehwaldt","sequence":"additional","affiliation":[{"name":"Departments of Surgery and Medicine, Third and Parnassus Avenues, University of California, San Francisco, CA 94143-0793; and Department of Genetics, Clinical Research Building, University of Pennsylvania, 415 Curie Boulevard, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H.","family":"Kazazian","sequence":"additional","affiliation":[{"name":"Departments of Surgery and Medicine, Third and Parnassus Avenues, University of California, San Francisco, CA 94143-0793; and Department of Genetics, Clinical Research Building, University of Pennsylvania, 415 Curie Boulevard, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. 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