# Physiological and therapeutic effects of ANGPTL3 variants in mice and humans

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $767,297

## Abstract

PROJECT SUMMARY
The discovery of new and effective treatments for coronary heart disease (CHD), the leading cause of death in
the world, requires the identification of novel disease mechanisms. Using genome-wide association studies
(GWASs) in large population cohorts and exome sequencing in individuals with an unusual lipid pattern that we
have termed “familial combined hypolipidemia”—extremely low blood lipids across the board but otherwise
healthy—we identified the ANGPTL3 (angiopoietin-like 3) gene as being linked to both blood triglyceride (TG)
and low-density lipoprotein cholesterol (LDL-C) levels. More recently, we have demonstrated that naturally
occurring loss-of-function mutations in ANGPTL3 are not only linked to lower TG and LDL-C levels but also to
substantial protection against CHD. Our work therefore recommends ANGPTL3 as a compelling therapeutic
target, perhaps rivalling or even surpassing the PCSK9 gene. ANGPTL3, a protein exclusively synthesized in
hepatocytes and secreted into the bloodstream, is well established to inhibit lipoprotein lipase, increasing blood
TG levels. The mechanism by which ANGPTL3 increases blood LDL-C levels remains to be determined. In
preliminary studies, we have begun to ascertain the effects of naturally occurring ANGPTL3 missense variants
using an Angptl3 knockout mouse model complemented with a physiological level of the human ANGPTL3
gene. We have found that specific missense variants have differing effects on TG and cholesterol levels in
mice, providing us with a means to distinguish between the physiological consequences of TG modulation and
LDL-C modulation in humans. We have also found that some missense variants inhibit ANGPTL3’s effects on
both TG and cholesterol levels, providing us with variants that we can attempt to individually introduce into
human hepatocytes in vivo with genome editing for therapeutic purposes.
Our specific aims are: (1) to assess the physiological effects of natural ANGPTL3 missense variants in mice;
(2) to assess the physiological effects of natural ANGPTL3 missense variants in humans; and (3) to use base
editing, a new type of genome editing, to introduce ANGPTL3 missense variants into human hepatocytes in
vivo. We will achieve these aims by employing a novel mouse model that can interrogate ANGPTL3 variants’
effects on TG and LDL-C levels; by taking advantage of the Penn Medicine BioBank cohort, in which ~12,000
individuals have been exome-sequenced—more than 500 of whom have ANGPTL3 missense variants—and
have given consent to be called back for potential participation in human physiological studies; and by building
on our expertise in base editing, paired with a chimeric liver-humanized mouse model, that will allow us to
interrogate the efficacy and safety of introducing ANGPTL3 variants into human hepatocytes in vivo—a novel
therapeutic approach that has the potential to yield a “vaccine” against CHD.

## Key facts

- **NIH application ID:** 10001632
- **Project number:** 5R01HL148769-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** MARINA CUCHEL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $767,297
- **Award type:** 5
- **Project period:** 2019-09-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10001632

## Citation

> US National Institutes of Health, RePORTER application 10001632, Physiological and therapeutic effects of ANGPTL3 variants in mice and humans (5R01HL148769-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10001632. Licensed CC0.

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