An oral antisense oligonucleotide for PCSK9 inhibition

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Fältnamn	Indikatorer	Metadata
000		04842naa a2200613 4500
001		oai:DiVA.org:liu-176171
003		SwePub
008		210609s2021 \| \|\|\|\|\|\|\|\|\|\|\|000 \|\|eng\|
024	7	a https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-1761712 URI
024	7	a https://doi.org/10.1126/scitranslmed.abe91172 DOI
040		a (SwePub)liu
041		a engb eng
042		9 SwePub
072	7	a ref2 swepub-contenttype
072	7	a art2 swepub-publicationtype
100	1	a Gennemark, Peteru Linköpings universitet,Avdelningen för medicinsk teknik,Tekniska fakulteten,AstraZeneca, Sweden4 aut0 (Swepub:liu)petge96
245	1 0	a An oral antisense oligonucleotide for PCSK9 inhibition
264	1	b AMER ASSOC ADVANCEMENT SCIENCE,c 2021
338		a print2 rdacarrier
500		a Funding Agencies\|AstraZenecaAstraZeneca; Ionis Pharmaceuticals
520		a Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce low-density lipoprotein (LDL) cholesterol and are used for treatment of dyslipidemia. Current PCSK9 inhibitors are administered via subcutaneous injection. We present a highly potent, chemically modified PCSK9 antisense oligonucleotide (ASO) with potential for oral delivery. Past attempts at oral delivery using earlier-generation ASO chemistries and transient permeation enhancers provided encouraging data, suggesting that improving potency of the ASO could make oral delivery a reality. The constrained ethyl chemistry and liver targeting enabled by N-acetylgalactosamine conjugation make this ASO highly potent. A single subcutaneous dose of 90 mg reduced PCSK9 by >90% in humans with elevated LDL cholesterol and a monthly subcutaneous dose of around 25 mg is predicted to reduce PCSK9 by 80% at steady state. To investigate the feasibility of oral administration, the ASO was coformulated in a tablet with sodium caprate as permeation enhancer. Repeated oral daily dosing in dogs resulted in a bioavailability of 7% in the liver (target organ), about fivefold greater than the plasma bioavailability. Target engagement after oral administration was confirmed by intrajejunal administration of a rat-specific surrogate ASO in solution with the enhancer to rats and by plasma PCSK9 and LDL cholesterol lowering in cynomolgus monkey after tablet administration. On the basis of an assumption of 5% liver bioavailability after oral administration in humans, a daily dose of 15 mg is predicted to reduce circulating PCSK9 by 80% at steady state, supporting the development of the compound for oral administration to treat dyslipidemia.
650	7	a MEDICIN OCH HÄLSOVETENSKAPx Medicinska och farmaceutiska grundvetenskaperx Farmaceutiska vetenskaper0 (SwePub)301012 hsv//swe
650	7	a MEDICAL AND HEALTH SCIENCESx Basic Medicinex Pharmaceutical Sciences0 (SwePub)301012 hsv//eng
700	1	a Walter, Katrinu AstraZeneca, Sweden4 aut
700	1	a Clemmensen, Niclasu AstraZeneca, Sweden4 aut
700	1	a Rekic, Dinkou AstraZeneca, Sweden4 aut
700	1	a Nilsson, Catarina A. M.u AstraZeneca, Sweden4 aut
700	1	a Knochel, Janeu AstraZeneca, Sweden4 aut
700	1	a Holtta, Mikkou AstraZeneca, Sweden4 aut
700	1	a Wernevik, Lindau AstraZeneca, Sweden4 aut
700	1	a Rosengren, Birgittau AstraZeneca, Sweden4 aut
700	1	a Kakol-Palm, Dorotau AstraZeneca, Sweden4 aut
700	1	a Wang, Yanfengu Ionis Pharmaceut Inc, CA 92010 USA4 aut
700	1	a Yu, Rosie Z.u Ionis Pharmaceut Inc, CA 92010 USA4 aut
700	1	a Geary, Richard S.u Ionis Pharmaceut Inc, CA 92010 USA4 aut
700	1	a Riney, Stan J.u Ionis Pharmaceut Inc, CA 92010 USA4 aut
700	1	a Monia, Brett P.u Ionis Pharmaceut Inc, CA 92010 USA4 aut
700	1	a Isaksson, Rikardu AstraZeneca, Sweden4 aut
700	1	a Jansson-Lofmark, Rasmusu AstraZeneca, Sweden4 aut
700	1	a Rocha, Cristina S. J.u AstraZeneca, Sweden4 aut
700	1	a Linden, Danielu AstraZeneca, Sweden4 aut
700	1	a Hurt-Camejo, Evau AstraZeneca, Sweden4 aut
700	1	a Crooke, Rosanneu Ionis Pharmaceut Inc, CA 92010 USA4 aut
700	1	a Tillman, Lloydu Ionis Pharmaceut Inc, CA 92010 USA4 aut
700	1	a Ryden-Bergsten, Tinau AstraZeneca, Sweden4 aut
700	1	a Carlsson, Bjornu AstraZeneca, Sweden4 aut
700	1	a Andersson, Ulfu AstraZeneca, Sweden4 aut
700	1	a Elebring, Marieu AstraZeneca, Sweden4 aut
700	1	a Tivesten, Annau AstraZeneca, Sweden4 aut
700	1	a Davies, Nigelu AstraZeneca, Sweden4 aut
710	2	a Linköpings universitetb Avdelningen för medicinsk teknik4 org
773	0	t Science Translational Medicined : AMER ASSOC ADVANCEMENT SCIENCEg 13:593q 13:593x 1946-6234x 1946-6242
856	4 8	u https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-176171
856	4 8	u https://doi.org/10.1126/scitranslmed.abe9117

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