Author + information
- Received January 16, 2019
- Revision received May 11, 2019
- Accepted May 15, 2019
- Published online October 28, 2019.
- Xiao Wang, PhD and
- Kiran Musunuru, MD, PhD, MPH, ML∗ ()
- Department of Medicine and Department of Genetics, Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
- ↵∗Address for correspondence:
Dr. Kiran Musunuru, Department of Medicine and Department of Genetics, Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Boulevard, Building 421, 11-104 Smilow Center, Philadelphia, Pennsylvania 19104.
• Individuals with ANGPTL3 loss-of-function mutations have reduced cholesterol levels, triglyceride levels, and risk of coronary heart disease, making ANGPTL3 a potential therapeutic target.
• An antisense oligonucleotide inhibitor of ANGPTL3 and a monoclonal antibody against ANGPTL3 have been advanced into clinical trials, with encouraging results to date.
• A distinct approach to targeting ANGPTL3 would be therapeutic gene editing in patients to induce permanent loss of function mutations mimicking those in individuals with naturally occurring cardioprotective mutations.
Hyperlipidemia is a major causal risk factor for atherosclerosis and coronary heart disease (CHD). Angiopoietin-like 3 (ANGPTL3) has emerged as a promising molecular target to reduce CHD risk due to its regulation of all 3 major lipid traits: low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides. Here, the authors review the discovery of ANGPTL3, the role of ANGPTL3 in lipoprotein metabolism, and the genetic association between naturally occurring ANGPTL3 loss-of-function mutations and CHD. In light of the favorable consequences of ANGPTL3 deficiency, various therapeutic strategies to target ANGPTL3 are currently in development, including a monoclonal antibody, an antisense oligonucleotide, and gene editing.
Dr. Musunuru is an unpaid scientific advisor to Verve Therapeutics. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received January 16, 2019.
- Revision received May 11, 2019.
- Accepted May 15, 2019.
- 2019 The Authors