In anticipation of planned upcoming Phase II clinical trials, we have completed a project in the past year on potential biomarkers for monitoring recombinant LCAT therapy. Because one target population for the drug are patients with a genetic defect in LCAT, namely Familial LCAT Deficiency (FLD), we have investigated whether LpX contributes to the renal disease in these patients. Unlike other lipoproteins that have micelle-like configuration of lipids with a neutral lipid core of cholesterol esters, LpX is rich in free cholesterol and forms multi-vesicular structures along with phospholipid. LCAT-KO mice unlike FLD patients do not accumulate LpX and do not develop renal disease, but we found that administration of exogenous LpX in these mice causes its accumulation in plasma compared to WT mice. Furthermore, the exogenous LpX is deposited in the kidney where it causes podocyte damage and severe proteinuria, indicating that monitoring plasma levels of LpX may be useful when treating FLD patients with recombinant LCAT. We also investigated the effect of LCAT in two different animal models of atherosclerosis and Alzheimer's disease and have published these findings. Started a collaboration with NCATS in developing small molecule activators of LCAT and have developed an assay suitable for high throughput screening of a chemical library.
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