title: Targeting APOC3 in the familial chylomicronemia syndrome.
abstract: The familial chylomicronemia syndrome is a genetic disorder characterized by severe hypertriglyceridemia and recurrent pancreatitis due to a deficiency in lipoprotein lipase (LPL). Currently, there are no effective therapies except for extreme restriction in the consumption of dietary fat. Apolipoprotein C-III (APOC3) is known to inhibit LPL, although there is also evidence that APOC3 increases the level of plasma triglycerides through an LPL-independent mechanism. We administered an inhibitor of APOC3 messenger RNA (mRNA), called ISIS 304801, to treat three patients with the familial chylomicronemia syndrome and triglyceride levels ranging from 1406 to 2083 mg per deciliter (15.9 to 23.5 mmol per liter). After 13 weeks of study-drug administration, plasma APOC3 levels were reduced by 71 to 90% and triglyceride levels by 56 to 86%. During the study, all patients had a triglyceride level of less than 500 mg per deciliter (5.7 mmol per liter) with treatment. These data support the role of APOC3 as a key regulator of LPL-independent pathways of triglyceride metabolism.
authors.affiliation: From the ECOGENE-21 Clinical Research Center, Chicoutimi Hospital, Chicoutimi, and the Department of Medicine, Université de Montréal, Montreal - both in Canada (D.G., D.B., K.T.); and Isis Pharmaceuticals, Carlsbad (V.J.A., W.S., S.G.H., R.S.G., B.F.B., M.J.G., R.M.C.), and the Department of Medicine, Division of Endocrinology-Metabolism, University California, San Diego, School of Medicine, La Jolla (J.L.W.) - both in California.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gaudet
authors.forename: Diane
authors.initials: D
authors.lastname: Brisson
authors.forename: Karine
authors.initials: K
authors.lastname: Tremblay
authors.forename: Veronica J
authors.initials: VJ
authors.lastname: Alexander
authors.forename: Walter
authors.initials: W
authors.lastname: Singleton
authors.forename: Steven G
authors.initials: SG
authors.lastname: Hughes
authors.forename: Richard S
authors.initials: RS
authors.lastname: Geary
authors.forename: Brenda F
authors.initials: BF
authors.lastname: Baker
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Graham
authors.forename: Rosanne M
authors.initials: RM
authors.lastname: Crooke
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Witztum
mesh_terms: D053305:Apolipoprotein C-III / Q000037:antagonists & inhibitors* / Q000097:blood; D006801:Humans; D008072:Hyperlipoproteinemia Type I / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D008071:Lipoprotein Lipase / Q000172:deficiency* / Q000235:genetics; D009154:Mutation; D009841:Oligonucleotides / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors*; D014280:Triglycerides / Q000097:blood*
chemical_list: D053305:Apolipoprotein C-III; C000593612:ISIS 304801; D009841:Oligonucleotides; D012333:RNA, Messenger; D014280:Triglycerides; D008071:Lipoprotein Lipase