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Analysis of new compounds to treat familial hypercholesterolemia

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41HL156602-01
Agency Tracking Number: R41HL156602
Amount: $296,495.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: NHLBI
Solicitation Number: PA17-131
Solicitation Year: 2017
Award Year: 2020
Award Start Date (Proposal Award Date): 2020-08-01
Award End Date (Contract End Date): 2021-07-31
Small Business Information
Hollywood, SC 29449-5869
United States
DUNS: 117182450
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 (414) 477-9108
Business Contact
Phone: (414) 477-9108
Research Institution
United States

 Nonprofit college or university

The long-term goal of the current proposal is to generate a new class of small molecules to treat
familial hypercholesterolemia. Familial hypercholesterolemia (FH) patients suffer from
excessively high levels of Low Density Lipoprotein Cholesterol (LDL-C), which if left untreated
results in death from severe cardiovascular disease. FH is caused primarily by mutations in the
LDL receptor (LDLR) that prevent the uptake and clearance of LDL-C by the liver. Although 4
major classes of LDL-C lowering drugs exist, (statins, bile acid sequestrants, PCSK9 inhibitors,
and cholesterol absorption inhibitors), all are inefficient at treating FH patients with homozygous
LDLR gene mutations (hoFH). Two new drugs, Lomitapide and Mipomersin, have recently been
approved for hoFH treatment. Both act independently of the LDLR to control lipoprotein
production by regulating APOB levels. Unfortunately, both drugs have serious side effects
including accumulation of liver triglycerides, which result in hepatic steatosis, elevated liver
enzyme levels, and liver damage. With hoFH occurring at frequency of up to 1/160K live births,
there is a need for new treatments that are safe and effective.
The identification of novel small molecules to treat hoFH, has been hampered by the lack of a
drug discovery platform that can recapitulate the deficiencies in liver function and cholesterol
metabolism that are present in FH patients. To circumvent this barrier, we generated induced
pluripotent stem cells from a hoFH patient. When the hoFH iPSCs were induced to form
hepatocytes, they recapitulated the pathophysiology of FH in culture. We used this platform to
screen a proprietary drug library and identified a family of structurally related small molecules
that could reproducibly reduce the production of Apolipoprotein B, which is the central protein
component of LDL-C. Preliminary studies demonstrate that these small molecules are highly
effective, do not cause abnormal lipid accumulation, have a novel mechanism of action, and a
chemical structure that is unrelated to any known cholesterol lowering drug.
In this phase I STTR application, we propose pre-clinical studies to test the hypothesis that our
lead compounds can effectively lower LDL-cholesterol and improve symptoms in physiologically
relevant in vivo models.NARRATIVE
We have identified a series of novel compounds that we believe are capable of reducing Low
Density Lipoprotein Cholesterol (LDL-C) in homozygous familial hypercholesterolemia (hoFH)
hepatocytes. We propose to determine whether these compounds are effective treatments in
mouse models of hypercholesterolemia and atherosclerosis.

* Information listed above is at the time of submission. *

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