Anti-ANGPTL3 Treatment for Cardiometabolic Disease

A University of Pittsburgh researcher has identified a novel treatment strategy for cardiometabolic disease including heart failure with preserved ejection fraction (HFpEF). Building on a recent discovery of factors expressed from the heart that can drive liver dysfunction and promote HFpEF progression, novel targets have been identified. Directed treatment of these targets using monoclonal antibodies or other approaches could prevent the progression of HFpEF and dramatically improve outcomes in those living with HFpEF.

Angptl3 secretion from heart tissue has been identified as a driver or HFpEF. Inhibition of ANGPTL3 expression using evinacumab can reduce plasma cholesterol in WT mice and could be a novel treatment strategy for patients with HFpEF.

Description

HFpEF is responsible for over half of all heart failure cases in the United States. Despite this high prevalence, no HFpEF specific medications exist with current treatment strategies focused on the management of comorbidities known to promote HFpEF progression (e.g., obesity and type 2 diabetes). Previous work has identified the role of liver dysfunction in HFpEF progression. With the recent discovery of a novel heart-to-liver signaling pathway as a potential therapeutic target, the lipid metabolism regulator angiopoietin-like protein 3 (Angptl3), has been identified. Inhibition of Angptl3 expression can directly treat HFpEF and could revolutionize the treatment of the millions of patients living with cardiometabolic disease.

Applications

- Cardiometabolic disease e.g., heart failure with preserved ejection fraction (HFpEF)
- Metabolic dysfunction-associated liver disease (MASLD)
- Combination cardiac-hepatic indication
- Diagnostic or patient-stratification use

Advantages

Direct treatment of HFpEF is an unmet clinical need. Currently, clinicians treat comorbidities and risk factors to reduce HFpEF progression. This approach fails to treat the underlying cause of HFpEF and risks adverse events due to polypharmacy.

Recent work identified Gcn5l1 as a protective heart-specific factor. In mice models of HFpEF when Gcn5l1 is deleted from cardiomyocytes (cKO), cardiac dysfunction was exacerbated. Of note, cKO mice increased the expression of a key lipid metabolism regulator, Angptl3, disrupting Angptl3-regulated lipase activity, resulting in cholesterol-mediated liver steatosis. This novel treatment approach directly inhibits Angptl3 expression and can directly modify the course of HFpEF progression.

Invention Readiness

In cKO mice, elevated levels of Angptl3 were discovered in the hearts and livers of HFpEF mice resulting in reduction in both lipoprotein lipase (LPL) production and activity and other proteins responsible for cholesterol metabolism. In wildtype (WT) HFpEF mice, treatment with evinacumab, an Angptl3 inhibitor, rebalanced the Angptl3-LPL axis, reduced cardiac fibrosis, normalized liver cholesterol and liver weight, halted body weight progression, and improved insulin sensitivity. Further work is required to explore other Angptl3 inhibitors, including decoy receptors or gene therapies.

IP Status

Patent Pending

Related Publication(s)

Bugga, P., Mushala, B. A., Stoner, M. W., Manning, J. R., Bhattarai, N., Sharifi-Sanjani, M., Vandevender, A., Mooli, R. G., Ramakrishnan, S. K., Kaufman, B. A., Shiva, S. S., Happe, C. L., Mullet, S. J., Gelhaus, S. L., Jurczak, M. J., & Scott, I. (2025). Cardiac-specific GCN5L1 deficiency promotes MASLD in HFpEF. bioRxiv (Cold Spring Harbor Laboratory). https://doi.org/10.1101/2025.02.05.636634

Stewart, J. E., Islam, R., Meadows, E., Mogus, J. P., Velayutham, M., Khramtsov, V. V., Scott, I., Hollander, J. M., & Thapa, D. (2026). GCN5L1-Mediated Lysine Acetylation Regulates Mitochondrial Bioenergetics and Redox Homeostasis in the Aged Heart. Antioxidants (Basel, Switzerland), 15(4), 481. https://doi.org/10.3390/antiox15040481