Familial lecithin:cholesterol acyltransferase deficiency: First-in-human treatment with enzyme replacement

Autor: Brian R. Krause, Alan T. Remaley, Robert D. Shamburek, Lita A. Freeman, Marcelo Amar, Reynold Homan, Bruce J. Auerbach, Rebecca Bakker-Arkema
Rok vydání: 2016
Předmět:
Male
0301 basic medicine
medicine.medical_specialty
Anemia
Endocrinology
Diabetes and Metabolism
Sterol O-acyltransferase
030204 cardiovascular system & hematology
Kidney
Article
Phosphatidylcholine-Sterol O-Acyltransferase
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Lecithin Cholesterol Acyltransferase Deficiency
Internal medicine
Internal Medicine
Humans
Medicine
Lipoprotein-X
Lecithin cholesterol acyltransferase deficiency
Hematologic Tests
Nutrition and Dietetics
Triglyceride
business.industry
Cholesterol
Cholesterol
HDL
Middle Aged
medicine.disease
Recombinant Proteins
030104 developmental biology
Postprandial
medicine.anatomical_structure
Endocrinology
chemistry
Disease Progression
lipids (amino acids
peptides
and proteins)
Safety
Cardiology and Cardiovascular Medicine
business
Zdroj: Journal of Clinical Lipidology. 10:356-367
ISSN: 1933-2874
DOI: 10.1016/j.jacl.2015.12.007
Popis: 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.
Databáze: OpenAIRE
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