Familial lecithin:cholesterol acyl-transferase (LCAT) deficiency, also known as FLD, is a rare, inherited disease in which people have abnormally low levels of high-density lipoprotein (“good”) cholesterol. FLD causes vision problems, kidney failure and anemia. Patients with FLD have a genetic defect in LCAT, an enzyme required to make normal cholesterol. Currently, no approved treatment exists for FLD. The investigators have developed a man-made version of the natural LCAT enzyme as a replacement therapy for FLD. This project involves studying the effects of the potential treatment in mouse and human blood samples.
The objective of this project is to provide effective enzyme replacement therapy (ERT) using recombinant human LCAT for patients with inherited mutations in the LCAT gene. These mutations result in FLD. FLD patients have drastically reduced high-density lipoprotein (HDL) cholesterol levels and develop corneal opacities, anemia, proteinuria or renal dysfunction. Glomerulosclerosis, the major cause of morbidity and mortality in FLD patients, may lead to renal failure in the fourth or fifth decade of life and necessitate dialysis or kidney transplantation.
The investigators produced rhLCAT and have obtained proof-of-principle data for ERT using LCAT-knockout mice, an animal model of FLD. They also have incubated rhLCAT in vitro with plasma from FLD patients, which resulted in the normalization of the lipoprotein profile. These data allowed them to obtain Orphan Drug Designation for rhLCAT for the treatment of FLD patients. The research team also has submitted an Investigational New Drug application to the Food and Drug Administration (FDA) for this indication.
In response to the application, the FDA requested a multiple-dose phase I study in FLD-affected patients, followed by a long-term extension study in the same patients. The FDA also requested a six-month toxicology study in LCAT-deficient mice. To enable these studies, the investigators must systematically assess the risk of an unwanted immune response to rhLCAT. Regulations and guidelines have been established for the development of immunoassays that detect, quantify and characterize antibody responses to therapeutic proteins, such as rhLCAT. BrIDGs will provide resources and expertise for the design and optimization of such immunoassays to detect and characterize anti-LCAT antibodies from human and murine plasma samples.
AlphaCore Pharma, LLC, Ann Arbor, Michigan
Brian R. Krause, Ph.D.
Public Health Impact
FLD occurs in individuals with a defective gene responsible for expressing the enzyme LCAT. The disease is characterized by cloudy corneas, anemia and eventually failure of the kidneys. AlphaCore Pharma is developing a form of LCAT, manufactured by biotechnological processes, to stop the loss of kidney function.
MedImmune, part of AstraZeneca, acquired AlphaCore Pharma in 2013 and accepted responsibility for the completion of this project.
- Pharmacokinetic/absorption, distribution, metabolism, and excretion (PK/ADME) studies