{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T04:16:55Z","timestamp":1791605815913,"version":"4.3.4"},"reference-count":38,"publisher":"SAGE Publications","issue":"2","license":[{"start":{"date-parts":[[2019,3,29]],"date-time":"2019-03-29T00:00:00Z","timestamp":1553817600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2019,3,29]],"date-time":"2019-03-29T00:00:00Z","timestamp":1553817600000},"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":["Nucleic Acid Therapeutics"],"published-print":{"date-parts":[[2019,4,1]]},"abstract":"<jats:p>\n                    Kallikrein is the key contact system mediator responsible for the conversion of high-molecular-weight kininogen into the inflammatory vasodilator peptide bradykinin, a process regulated by C1-esterase inhibitor (C1-INH). In hereditary angioedema (HAE), genetic mutations result in deficient or dysfunctional C1-INH and dysregulation of the contact system leading to recurrent, sometimes fatal, angioedema attacks. IONIS-PKK\n                    <jats:sub>Rx<\/jats:sub>\n                    is a second-generation 2\u2032-O-(2-methoxyethyl)-modified chimeric antisense oligonucleotide, designed to bind and selectively reduce prekallikrein (\n                    <jats:italic toggle=\"yes\">PKK<\/jats:italic>\n                    ) mRNA in the liver. IONIS-PKK\n                    <jats:sub>Rx<\/jats:sub>\n                    demonstrated dose-dependent reduction of human prekallikrein hepatic mRNA and plasma protein in transgenic mice and dose- and time-dependent reductions of plasma PKK in Cynomolgus monkeys. Similar dose-dependent reductions of plasma PKK levels were observed in healthy human volunteers accompanied by decreases in bradykinin generation capacity with an acceptable safety and tolerability profile. These results highlight a novel and specific approach to target PKK for the treatment of HAE and other diseases involving contact system activation and overproduction of bradykinin.\n                  <\/jats:p>","DOI":"10.1089\/nat.2018.0754","type":"journal-article","created":{"date-parts":[[2019,2,28]],"date-time":"2019-02-28T15:52:30Z","timestamp":1551369150000},"page":"82-91","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":33,"title":["IONIS-PKK\n                    <sub>Rx<\/sub>\n                    a Novel Antisense Inhibitor of Prekallikrein and Bradykinin Production"],"prefix":"10.1177","volume":"29","author":[{"given":"Jason D.","family":"Ferrone","sequence":"first","affiliation":[{"name":"Ionis Pharmaceuticals, Inc., Carlsbad, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gourab","family":"Bhattacharjee","sequence":"additional","affiliation":[{"name":"Ionis Pharmaceuticals, Inc., Carlsbad, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexey S.","family":"Revenko","sequence":"additional","affiliation":[{"name":"Ionis Pharmaceuticals, Inc., Carlsbad, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas A.","family":"Zanardi","sequence":"additional","affiliation":[{"name":"Ionis Pharmaceuticals, Inc., Carlsbad, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marshelle S.","family":"Warren","sequence":"additional","affiliation":[{"name":"Ionis Pharmaceuticals, Inc., Carlsbad, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederick J.","family":"Derosier","sequence":"additional","affiliation":[{"name":"Ionis Pharmaceuticals, Inc., Carlsbad, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas J.","family":"Viney","sequence":"additional","affiliation":[{"name":"Ionis Pharmaceuticals, Inc., Carlsbad, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nguyen C.","family":"Pham","sequence":"additional","affiliation":[{"name":"Ionis Pharmaceuticals, Inc., Carlsbad, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gwendolyn E.","family":"Kaeser","sequence":"additional","affiliation":[{"name":"Ionis Pharmaceuticals, Inc., Carlsbad, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brenda F.","family":"Baker","sequence":"additional","affiliation":[{"name":"Ionis Pharmaceuticals, Inc., Carlsbad, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugene","family":"Schneider","sequence":"additional","affiliation":[{"name":"Ionis Pharmaceuticals, Inc., Carlsbad, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven G.","family":"Hughes","sequence":"additional","affiliation":[{"name":"Ionis Pharmaceuticals, Inc., Carlsbad, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brett P.","family":"Monia","sequence":"additional","affiliation":[{"name":"Ionis Pharmaceuticals, Inc., Carlsbad, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. 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