# Analysis of new compounds to treat familial hypercholesterolemia

> **NIH NIH R41** · GRUTHAN BIOSCIENCE LLC · 2020 · $296,495

## Abstract

PROJECT SUMMARY
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.

## Key facts

- **NIH application ID:** 10073063
- **Project number:** 1R41HL156602-01
- **Recipient organization:** GRUTHAN BIOSCIENCE LLC
- **Principal Investigator:** STEPHEN A DUNCAN
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $296,495
- **Award type:** 1
- **Project period:** 2020-08-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10073063

## Citation

> US National Institutes of Health, RePORTER application 10073063, Analysis of new compounds to treat familial hypercholesterolemia (1R41HL156602-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10073063. Licensed CC0.

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