# Targeted editing of ASGR1 for cardiovascular diseases

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2024 · $722,150

## Abstract

PROJECT SUMMARY/ABSTRACT
The contribution of low density lipoproteins (LDL) and very low density lipoproteins (VLDL) to the development
of cardiovascular disease (CVD) is critical in atherogenesis. Recent therapeutic advances considerably
reduced the incidence of CVD. Despite the progress of clinical treatments in the past 30 years, for a significant
proportion of statin-treated patients, relatively high residual risk remains, likely associated with persistent
relatively high levels of triglyceride (TG), thus limiting the benefits of these therapies. This underscores the
need for additional new therapies targeting lipid metabolism in CVD prevention and treatment. ASGR1 has
emerged as a new promising target for dyslipidemia to control CVD risk. ASGR1 encodes asialoglycoprotein
receptor type 1, which is mainly expressed on the basolateral membrane of hepatocytes, where it facilitates the
uptake of circulating glycoproteins. The loss-of-function (LoF) mutations in ASGR1 were found to be
associated with lowering of non-HDL-C levels and a reduced risk of CVD. The beneficial effects of ASGR1
deficiency in lowering TG and TC levels were further demonstrated in mice and pigs. In this project, we
propose to develop a “One-Shot for Cure” to treat hyperlipidemia and CVD by targeting ASGR1 with a base
editing approach delivered via engineered viral-like particles (eVLPs). Specifically, we will develop eVLP-BE-
ASGR1 therapy in a preclinical model species, the New Zealand White rabbits. We will determine the optimal
targeting strategies using in vitro cultured rabbit cells, followed by experiments to determine the optimal
delivery parameters to achieve effective ASGR1 gene knockout in rabbit hepatocytes. We will determine the
efficacy of eVLP-BE-ASGR1 therapy in rabbit atherosclerosis model and establish the long-term safety profile
of eVLP-BE-ASGR1 therapy in rabbits. Utilizing the latest breakthroughs in base editing and non-viral eVLP
technologies, the successful accomplishment of these objectives will yield compelling evidence, enabling the
development of a revolutionary “One-Shot for Cure” therapy aimed at treating hyperlipidemia and CVD through
the precise targeting of ASGR1.

## Key facts

- **NIH application ID:** 10880949
- **Project number:** 1R01HL169976-01A1
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** YUQING Eugene CHEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $722,150
- **Award type:** 1
- **Project period:** 2024-03-15 → 2028-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10880949

## Citation

> US National Institutes of Health, RePORTER application 10880949, Targeted editing of ASGR1 for cardiovascular diseases (1R01HL169976-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10880949. Licensed CC0.

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