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ANGPTL3: A Breakthrough Target in Treatment for Dyslipidemia and Atherosclerosis
Hirotaka Fukami1, Yuichi Oike1,2,3
1Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University.
Insights
Targeting Angiopoietin-like protein 3 (ANGPTL3) offers a novel approach to managing dyslipidemia, particularly for patients resistant to standard treatments. This strategy effectively lowers LDL-C and triglyceride levels, reducing cardiovascular disease risk.
Area of Science:
- Biochemistry
- Pharmacology
- Cardiovascular Medicine
Background:
- Dyslipidemia is a primary risk factor for atherosclerosis and cardiovascular disease (CVD).
- Familial hypercholesterolemia (FH) patients often show resistance to conventional lipid-lowering therapies like statins, ezetimibe, and PCSK9 inhibitors.
- Insufficiently lowered LDL-C levels in resistant cases contribute to CVD development.
Purpose of the Study:
- To review emerging therapeutic strategies targeting Angiopoietin-like protein 3 (ANGPTL3) for treatment-resistant dyslipidemia.
- To highlight ANGPTL3 inhibition as a novel approach to reduce LDL-C and triglyceride levels, independent of LDL receptor function.
- To discuss the potential of ANGPTL3-targeted therapies in preventing CVD in high-risk populations.
Main Methods:
- Review of current literature on ANGPTL3 biology and its role in lipid metabolism.
- Analysis of clinical trial data for ANGPTL3-targeted therapeutics, including monoclonal antibodies (evinacumab) and siRNA (zodasiran, solbinsiran).
- Examination of preclinical data for a novel peptide-based anti-ANGPTL3 vaccine in a familial hypercholesterolemia mouse model.
Main Results:
- ANGPTL3 inhibition effectively reduces LDL-C and triglyceride levels by enhancing lipoprotein clearance.
- Evinacumab demonstrated significant LDL-C and TG reduction in FH patients resistant to conventional treatments.
- siRNA therapeutics and a preclinical peptide-based vaccine show promise in improving lipid profiles and reducing atherosclerotic burden.
Conclusions:
- ANGPTL3 inhibition represents a promising therapeutic avenue for managing treatment-resistant dyslipidemia.
- These novel therapies offer a potential strategy to overcome limitations of current treatments and reduce cardiovascular risk.
- Further development of ANGPTL3-targeted agents could significantly impact the management of high-risk cardiovascular patients.
Abstract:
Dyslipidemia is a major risk factor for atherosclerosis and subsequent cardiovascular disease (CVD). Despite conventional treatment with statins, ezetimibe, or PCSK9 inhibitors, there are cases of familial hypercholesterolemia (FH) in which LDL-C levels cannot be sufficiently lowered to the target level, resulting in failure to prevent CVD. Inhibition of Angiopoietin-like protein 3 (ANGPTL3) has emerged as a new therapeutic strategy to reduce LDL-C levels independent of the LDL receptor function. Since ANGPTL3 suppresses lipoprotein lipase (LDL) and endothelial lipase (EL) activities, its inhibition facilitates the clearance of very low-density lipoprotein cholesterol, decreasing both LDL-C and triglyceride (TG) levels. In fact, evinacumab, an anti-ANGPTL3 monoclonal antibody, has been shown to substantially reduce LDL-C and TG levels, even in FH patients with LDL receptor gene mutations who are resistant to the conventional treatments described above. Clinical trials have also shown that siRNA therapeutics, such as zodasiran and solbinsiran, improve lipid profiles in patients with dyslipidemia. Recently, we have begun developing a peptide-based anti-ANGPTL3 vaccine and confirmed in a preclinical FH mouse model that it significantly decreases LDL-C and TG levels, reduces atherosclerotic lesions and maintains long-term efficacy without adverse effects. In this review, we discuss the promising advances in ANGPTL3-targeted therapeutics that may overcome treatment-resistant dyslipidemia and reduce CVD risk in high-risk populations.
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