ApoC-II mimetic peptides
Inventors
Remaley, Alan Thomas • Ghosh, Soumitra Shanker • Devalaraja, Madhav N. • Lo, Chih-Hung • Sviridov, Denis O. • Wolska, Anna
Assignees
United State Of America REPRESENTED BY SECRETARY Department Of Health And Human Services AS • Novo Nordisk AS • US Department of Health and Human Services
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11827690-B2
Publication Date
2023-11-28
Expiration Date
2038-01-19
Abstract
The disclosure provides apolipoprotein C-II (apoC-II) mimetic peptides and methods for treating hypertriglyceridemia in a patient with an effective amount of an apoC-II mimetic peptide.
Core Innovation
The invention provides isolated apolipoprotein C-II (apoC-II) mimetic peptides capable of lowering triglyceride levels in vitro and in vivo. These peptides typically comprise a multihelical structure, with one or more helical domains being amphipathic to allow lipid and lipoprotein surface binding, and another helical domain responsible for activating lipoprotein lipase (LPL). Specifically, in typical embodiments, the peptides are bihelical comprising a first amphipathic helical domain, a hinge region, and a second helical domain that activates LPL.
The peptides are designed to treat hypertriglyceridemia, including common forms and those caused by genetic defects such as LPL or apoC-II deficiencies. A variety of amphipathic helices from apoC-II or variants thereof can be used as the first domain. Variants of helix 2 and helix 3 of apoC-II may include elongations, truncations, mutations (amino acid substitutions), and chemical modifications such as covalent linkage of fatty acids to increase lipid affinity and biological half-life. The peptides can also displace apoC-III from lipoproteins, allowing treatment of hypertriglyceridemia associated with elevated apoC-III levels.
The background indicates that hypertriglyceridemia, defined as serum triglyceride levels over 150 mg/dL, poses risks for cardiovascular disease and acute pancreatitis. Existing treatments like fibrates and omega-3 fatty acids have uncertain efficacy in reducing such risks. Hypertriglyceridemia can result from secondary causes such as obesity, diabetes, pregnancy, alcohol, and drugs, or from rare genetic defects in LPL or apoC-II. The invention addresses the need for new therapeutic agents that effectively lower triglyceride levels.
Claims Coverage
The patent contains one independent claim that defines the apoC-II mimetic peptide composition and its key features.
Isolated apoC-II mimetic peptide with defined structure and hinge region
An isolated apoC-II mimetic peptide of no more than 50 amino acids comprising from N-terminus to C-terminus a first amphipathic helical domain, a hinge region containing 3-15 amino acids including one or more norleucine residues, and a second helical domain, wherein the peptide is not the sequence of SEQ ID NO: 56.
Pharmaceutical composition containing the apoC-II mimetic peptide
A pharmaceutical composition comprising the above-described apoC-II mimetic peptide and a pharmaceutically acceptable carrier.
Method of treating hypertriglyceridemia with apoC-II mimetic peptide
A method of treating hypertriglyceridemia in a patient by administering an effective amount of the apoC-II mimetic peptide or the pharmaceutical composition containing it.
Treatment of hypertriglyceridemia associated with obesity
Use of the method for treating hypertriglyceridemia associated with obesity.
Treatment of hypertriglyceridemia associated with diabetes mellitus
Use of the method for treating hypertriglyceridemia associated with diabetes mellitus.
Treatment of patients at risk for or with acute cardiovascular disease
Use of the method for treating patients who have developed or are at risk for acute cardiovascular disease related to hypertriglyceridemia.
The claims cover isolated peptides with a specific amphipathic first domain, a hinge region with norleucine, and a second helical domain; pharmaceutical compositions thereof; and methods of treating hypertriglyceridemia and associated conditions using such peptides.
Stated Advantages
The peptides are capable of lowering triglyceride levels both in vitro and in vivo effectively.
The apoC-II mimetic peptides can activate lipoprotein lipase, promoting triglyceride hydrolysis efficiently, sometimes better than native apoC-II protein.
The peptides can displace apoC-III from lipoproteins, overcoming its inhibitory effect on lipolysis.
Chemical modifications enhance lipid binding affinity, therapeutic properties, and biological half-life of the peptides.
The peptides provide new therapeutic agents addressing hypertriglyceridemia caused by both common and genetic factors, overcoming limitations of existing treatments like fibrates and omega-3 fatty acids.
Documented Applications
Therapeutic treatment of hypertriglyceridemia in patients, including mild to very severe cases with fasting serum triglycerides above 150 mg/dL.
Treatment of hypertriglyceridemia associated with obesity, diabetes mellitus, alcohol consumption, and medication-induced cases.
Treatment of hypertriglyceridemia caused by genetic defects such as familial lipoprotein lipase deficiency, apoC-II deficiency, and elevated apoC-III levels.
Treatment of patients who have developed or are at risk for acute pancreatitis and acute cardiovascular disease.
Use in reducing post-prandial elevated triglyceride levels.
Interested in licensing this patent?