Lecithin Cholesterol Acyl Transferase (LCAT), a plasma enzyme that esterifies cholesterol, is critical in lipoprotein metabolism and in the removal of excess cholesterol form peripheral tissues. Familial LCAT Deficiency (FLD) is a rare (<1/200,000) autosomal recessive disorder that is associated with low HDL, anemia, corneal cholesterol deposits, splenomegaly and premature atherosclerosis. The main clinical problem arises from the formation of an abnormal lipoprotein particle called Lp-X, which gets trapped in the glomerulus and can cause end stage renal disease in the third or fourth decade of life. LCAT is an ideal candidate for enzyme replacement therapy, because it is a low abundant single subunit enzyme that acts in the plasma compartment. Only about 10-15% residual activity is necessary to prevent most manifestations of FLD, including renal disease. It is also relatively stable, both in vitro and in vivo. Its half-life in humans is approximately 3-4 days in humans. Based on transgenic animal studies in mice and rabbits, over expression (>100-fold) of LCAT does not appear to have any negative consequences. In the past year, our laboratory completed a pre-clinical animal study in LCAT K/O mice showing the feasibility of using recombinant LCAT as a therapeutic agent. In this study, a single IV bolus of recombinant into LCAT K/O mice was found to restore the rate of cholesterol esterification and stimulated the formation of a normal lipoprotein profile that persisted for several days. Most importantly, the abnormal Lp-X like particles that accumulate in the absence of LCAT were markedly decreased. The NIH has a patent on the therapeutic use of LCAT, which was licensed to AlphaCore Pharma (ACP). We have established a CRADA with ACP for developing recombinant LCAT as a therapeutic. It is anticipated the a single dose escalation Phase 1 trial of an intravenous preparation of recombinant LCAT will be started in 2011.
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