Abstract

Just prior to 2017, we completed and published a Phase I study of recombinant LCAT showing that it was safe and raised HDL-C. In addition we did the first enzyme replacement therapy of LCAT in a patient with Familial LCAT Deficiency, showing that it normalized their lipoprotein profile. Recombinant LCAT was licensed to MedImmune where it is now undergoing Phase II testing. In the past year, we developed an mouse model for LCAT deficiency that form high levels of LpX and spontaneously develop renal disease and showed that recombinant LCAT prevents renal disease in this model. A revised version of this paper is under review. We also published a paper describing a novel and more convenient assay for measuring LCAT activity that can be used in future clinical trials. We also identified the mechanism for activation of LCAT by a small molecule first identified by a large drug company and have identified several other novel small molecule activators of LCAT that we published and have patented.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAHL006092-09
Application #
9787932
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2018
Total Cost
Indirect Cost

  Institution

Name
U.S. National Heart Lung and Blood Inst
Department
Type
DUNS #
City
State
Country
Zip Code

  Publications

Sakurai, Toshihiro; Sakurai, Akiko; Vaisman, Boris L et al. (2018) Development of a novel fluorescent activity assay for lecithin:cholesterol acyltransferase. Ann Clin Biochem 55:414-421
Cooke, Allison L; Morris, Jamie; Melchior, John T et al. (2018) A thumbwheel mechanism for APOA1 activation of LCAT activity in HDL. J Lipid Res 59:1244-1255
Freeman, Lita A; Demosky Jr, Stephen J; Konaklieva, Monika et al. (2017) Lecithin:Cholesterol Acyltransferase Activation by Sulfhydryl-Reactive Small Molecules: Role of Cysteine-31. J Pharmacol Exp Ther 362:306-318
Shamburek, Robert D; Bakker-Arkema, Rebecca; Auerbach, Bruce J et al. (2016) Familial lecithin:cholesterol acyltransferase deficiency: First-in-human treatment with enzyme replacement. J Clin Lipidol 10:356-67
Ossoli, Alice; Neufeld, Edward B; Thacker, Seth G et al. (2016) Lipoprotein X Causes Renal Disease in LCAT Deficiency. PLoS One 11:e0150083
Shamburek, Robert D; Bakker-Arkema, Rebecca; Shamburek, Alexandra M et al. (2016) Safety and Tolerability of ACP-501, a Recombinant Human Lecithin:Cholesterol Acyltransferase, in a Phase 1 Single-Dose Escalation Study. Circ Res 118:73-82
Thacker, Seth G; Rousset, Xavier; Esmail, Safiya et al. (2015) Increased plasma cholesterol esterification by LCAT reduces diet-induced atherosclerosis in SR-BI knockout mice. J Lipid Res 56:1282-95
Stukas, Sophie; Freeman, Lita; Lee, Michael et al. (2014) LCAT deficiency does not impair amyloid metabolism in APP/PS1 mice. J Lipid Res 55:1721-9
Liu, Zheng; Thacker, Seth G; Fernandez-Castillejo, Sara et al. (2014) Synthesis of cholesterol analogues bearing BODIPY fluorophores by Suzuki or Liebeskind-Srogl cross-coupling and evaluation of their potential for visualization of cholesterol pools. Chembiochem 15:2087-96
Vaisman, Boris L; Remaley, Alan T (2013) Measurement of lecithin-cholesterol acyltransferase activity with the use of a Peptide-proteoliposome substrate. Methods Mol Biol 1027:343-52

Showing the most recent 10 out of 19 publications