Abstract

In the past year, we completed a protocol treating a single patient with Familial LCAT Deficiency with recombinant LCAT. There was no significant adverse events and the the recombinant LCAT behaved like expected based on studies of LCAT-KO mice in regard to its ability to increase HDL levels. The rLCAT treatment also restored cholesteryl ester levels to near normal levels and above threshold necessary to prevent LpX formation, the abnormal lipoprotein particle that accumulates in FLD and causes renal disease. Based on these results and a promising Phase I study done at the NIH, showing the safety of recombinant LCAT, AlphaCore Pharma, the original licensee of the NIH patent on recombinant LCAT, was acquired by AstraZeneca. In the past year, we have developed a CRADA with AstraZeneca and are now working with them on future plans for additional clinical trials of recombinant LCAT. In addition, we have started a collaboration with Dr. Monika Konaklieva at American University and have identified several small molecule activators of LCAT, which have potential therapeutic value. A provisional patent was filed on this work.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAHL006092-05
Application #
8939861
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
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