# Angiopoietin-like Protein 3 (ANGPTL3) Targeting in the Management of Dyslipidemias

## TL;DR

This paper reviews how targeting the ANGPTL3 protein can help manage dyslipidemia and reduce cardiovascular disease risk through various therapeutic approaches.

## Contribution

The paper provides an updated overview of ANGPTL3 inhibition strategies, including monoclonal antibodies, antisense oligonucleotides, and gene editing techniques.

## Key findings

- Inhibiting ANGPTL3 reduces LDL-cholesterol levels independently of the LDL receptor.
- Therapeutic approaches like monoclonal antibodies and antisense oligonucleotides show promising clinical results.
- CRISPR/Cas-based gene editing is a promising future strategy for targeting ANGPTL3.

## Abstract

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality, despite advances in pharmacological prevention and treatment. The burden of CVD necessitates implementing the treatment of risk factors including dyslipidemia. Pharmaceutical advancements and in depth understanding of pathophysiology have enabled innovative therapies targeting pathways underlying lipoprotein metabolism disorders. Angiopoietin protein-like 3 (ANGPTL3) plays a crucial role in the regulation of lipoprotein metabolism, therefore being a potential therapeutic target. Inhibition of ANGPTL3 has emerged as a new therapeutic strategy to reduce LDL-cholesterol levels independent of the LDL receptor function. Therapeutic approaches for ANGPTL3 inhibition range from monoclonal antibodies to nucleic acid therapeutics including antisense oligonucleotides and small interfering RNAs. In this review, we briefly explain the structure and mechanism of action of ANGPTL3 and discuss the therapeutic approaches for targeting ANGPTL3 in the clinical setting. We also discuss Evinacumab, a monoclonal antibody, its structure, mechanism of action, safety, tolerability, pharmacokinetics, and pharmacodynamics, as well as its clinical trial-derived results. The antisense oligonucleotides modify ANGPTL3 mRNA to inhibit protein production, and small interfering RNAs induce mRNA degradation; results from clinical trials were reviewed in detail. Finally, we discuss promising gene editing approaches including clustered regularly interspaced short palindromic repeats (CRISPR)/Cas systems.