title: Familial lecithin:cholesterol acyltransferase deficiency: First-in-human treatment with enzyme replacement.
abstract: BACKGROUND
  Humans with familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) have extremely low or undetectable high-density lipoprotein cholesterol (HDL-C) levels and by early adulthood develop many manifestations of the disorder, including corneal opacities, anemia, and renal disease.
  
  
  OBJECTIVE
  To determine if infusions of recombinant human LCAT (rhLCAT) could reverse the anemia, halt progression of renal disease, and normalize HDL in FLD.
  
  
  METHODS
  rhLCAT (ACP-501) was infused intravenously over 1 hour on 3 occasions in a dose optimization phase (0.3, 3.0, and 9.0 mg/kg), then 3.0 or 9.0 mg/kg every 1 to 2 weeks for 7 months in a maintenance phase. Plasma lipoproteins, lipids, LCAT levels, and several measures of renal function and other clinical labs were monitored.
  
  
  RESULTS
  LCAT concentration peaked at the end of each infusion and decreased to near baseline over 7 days. Renal function generally stabilized or improved and the anemia improved. After infusion, HDL-C rapidly increased, peaking near normal in 8 to 12 hours; analysis of HDL particles by various methods all revealed rapid sequential disappearance of preβ-HDL and small α-4 HDL and appearance of normal α-HDL. Low-density lipoprotein cholesterol increased more slowly than HDL-C. Of note, triglyceride routinely decreased after meals after infusion, in contrast to the usual postprandial increase in the absence of rhLCAT infusion.
  
  
  CONCLUSIONS
  rhLCAT infusions were well tolerated in this first-in-human study in FLD; the anemia improved, as did most parameters related to renal function in spite of advanced disease. Plasma lipids transiently normalized, and there was rapid sequential conversion of small preβ-HDL particles to mature spherical α-HDL particles.
authors.affiliation: Cardiovascular and Pulmonary Branch, National Heart, Lung and Blood Institute, NIH, Bethesda, MD, USA. Electronic address: bobs@mail.nih.gov.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Shamburek
authors.affiliation: AlphaCore Pharma, Ann Arbor, MI, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Bakker-Arkema
authors.affiliation: AlphaCore Pharma, Ann Arbor, MI, USA.
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Auerbach
authors.affiliation: AlphaCore Pharma, Ann Arbor, MI, USA.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Krause
authors.affiliation: AlphaCore Pharma, Ann Arbor, MI, USA.
authors.forename: Reynold
authors.initials: R
authors.lastname: Homan
authors.affiliation: Cardiovascular and Pulmonary Branch, National Heart, Lung and Blood Institute, NIH, Bethesda, MD, USA.
authors.forename: Marcelo J
authors.initials: MJ
authors.lastname: Amar
authors.affiliation: Cardiovascular and Pulmonary Branch, National Heart, Lung and Blood Institute, NIH, Bethesda, MD, USA.
authors.forename: Lita A
authors.initials: LA
authors.lastname: Freeman
authors.affiliation: Cardiovascular and Pulmonary Branch, National Heart, Lung and Blood Institute, NIH, Bethesda, MD, USA.
authors.forename: Alan T
authors.initials: AT
authors.lastname: Remaley
mesh_terms: D000740:Anemia / Q000150:complications; D008076:Cholesterol, HDL / Q000097:blood; D018450:Disease Progression; D006403:Hematologic Tests; D006801:Humans; D007668:Kidney / Q000187:drug effects; D007863:Lecithin Cholesterol Acyltransferase Deficiency / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D012449:Safety
chemical_list: D008076:Cholesterol, HDL; D011994:Recombinant Proteins; D007862:Phosphatidylcholine-Sterol O-Acyltransferase
keywords: Cholesterol; HDL; LCAT; Lecithin cholesterol acyltransferase; Lecithin cholesterol acyltransferase deficiency; Lipoprotein-X; Recombinant enzyme replacement; Renal disease; Triglyceride