Lipoprotein targeting protease inhibitors and uses
Inventors
Remaley, Alan T. • Gordon, Scott M.
Assignees
US Department of Health and Human Services
Publication Number
US-11872261-B2
Publication Date
2024-01-16
Expiration Date
2036-10-18
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Described herein is the design and construction of a class of lipoprotein targeting protease inhibitors. Small peptides with protease inhibitor activity are conjugated to hydrophobic, lipoprotein targeting molecules using, for instance, amine reactive chemistry. Methods of use of the resultant lipoprotein targeting protease inhibitor (antiprotease) molecules are also described. Also described is the production and use of protease inhibitor enriched HDL particles, as well as A1AT-peptide-enriched HDL particles, and their use in various therapeutic contexts.
Core Innovation
The invention describes the design and construction of a class of lipoprotein targeting protease inhibitors comprising small peptides with protease inhibitor activity conjugated to hydrophobic, lipoprotein targeting molecules such as vitamin E, acyl chains, or cholesterol, either directly or via a hydrophilic linker. These lipoprotein targeting protease inhibitor molecules can be used therapeutically, including formulations where peptides are contained in or part of lipoproteins, such as HDL particles. Methods of producing protease inhibitor enriched HDL particles by contacting them with such peptides are also provided.
The problem addressed originates from limitations in current treatments for cardiovascular diseases and alpha-1-antitrypsin (A1AT) deficiency. Cardiovascular disease is largely caused by atherosclerosis involving cholesterol accumulation and inflammation. Existing HDL therapies, including infusion of reconstituted HDL, face challenges such as high cost and intravenous delivery requirements, limiting use to acute treatment. Current A1AT deficiency treatment involves intravenous infusion of purified protein, which is expensive and only modestly effective. It has been shown that pre-incubation of A1AT with HDL improves treatment efficacy by enhancing targeting to lungs, highlighting a need for improved targeting of protease inhibitors to lipoproteins to optimize therapy.
Claims Coverage
The patent includes two independent claims focused on methods of treating alpha-1-antitrypsin deficiency or atherosclerosis using specific compositions.
Composition comprising specific vitamin E conjugated peptides for therapy
A method of treating alpha-1-antitrypsin (A1AT) deficiency or atherosclerosis by administering to a subject a composition comprising Vitamin E (VitE)-PEG-AAPV (SEQ ID NO: 5) or VitE-PEG-AAPV-CMK (SEQ ID NO: 6). The composition can be administered via injection or infusion.
Incorporation of compositions into implantable devices for therapy
A method of treating alpha-1-antitrypsin deficiency or atherosclerosis by administering a composition comprising the specified peptides in an implantable device, including but not limited to a stent.
The independent claims cover therapeutic methods employing vitamin E conjugated protease inhibitor peptides either by injection/infusion or via implantable devices, addressing treatment of A1AT deficiency and atherosclerosis.
Stated Advantages
Improved efficacy over current A1AT infusion treatment by targeting protease inhibitors to HDL, facilitating enhanced delivery to sites of inflammation such as the lung and vascular wall.
Increased potency due to multiple copies of the small peptide inhibitors being loadable onto each HDL particle, compared to one molecule of full-length A1AT per HDL particle.
Protection of the protease inhibitor activity by HDL binding, including resistance to oxidative inactivation of alpha-1-antitrypsin.
Potential to treat a broad range of protease-mediated diseases, including cardiovascular conditions, COPD, A1AT deficiency, and cancer.
Documented Applications
Treatment of cardiovascular diseases including atherosclerosis, coronary artery disease, peripheral vascular disease, acute coronary syndrome, and reperfusion myocardial injury.
Therapy for protease inhibitor deficiencies such as alpha-1-antitrypsin deficiency, emphysema, and chronic obstructive pulmonary disease (COPD).
Use in reducing inflammation and protease-mediated tissue damage through elastase inhibition.
Use in implantable devices, such as coatings or impregnation of vascular stents, for sustained local therapeutic release and treatment of dyslipidemic or vascular disorders.
Research applications to characterize structure and function of lipoproteins and protease inhibitor peptides.
Interested in licensing this patent?