US-12616713-B2 - Methods for enhancing vascular density

Abstract

The present invention relates to methods of increasing vascular density and/or blood flow in tissue of a subject, and to increasing exercise capacity of a subject, the methods include administering to a subject an effective amount of an agent that elevates SIRTI activity in endothelial cells of the subject, the invention further includes administering an NAD+ agonist or NAD+ precursor to a subject to increase vascular density and/or blood flow. The invention includes compositions comprising the said agent.

Inventors

• Lindsay Edward Wu
• David Andrew Sinclair
• Abhirup Das

Assignees

• METRO INTERNATIONAL BIOTECH, LLC

Dates

Publication Date

20260505

Application Date

20230120

Priority Date

20161221

Claims (20)

1. 1 . A method of treating hemorrhage in a subject in need thereof, the method comprising administering to the subject an effective amount of a pharmaceutical composition comprising nicotinic acid mononucleotide (NaMN).
2. 2 . The method of claim 1 , wherein the pharmaceutical composition is administered orally.
3. 3 . The method of claim 1 , wherein the NaMN is in crystalline form.
4. 4 . The method of claim 1 , wherein the pharmaceutical composition is in the form of a tablet, a troche, a lozenge, a dispersible powder or granule, a hard capsule.
5. 5 . The method of claim 1 , wherein the pharmaceutical composition further comprises GYY4137, sodium hydrosulfide, or pharmaceutically acceptable salts thereof.
6. 6 . The method of claim 1 , wherein the pharmaceutical composition is in the form of a tablet, a troche, a lozenge, an aqueous or oily suspension, a dispersible powder or granule, an emulsion, a hard or soft capsule, or a syrup or elixir.
7. 7 . The method of claim 1 , wherein the pharmaceutical composition is in the form of a sterile injectable aqueous suspension, or a sterile injectable oleaginous suspension, or a sterile injectable aqueous solution, or a sterile injectable non-aqueous solution, or a sterile injectable non-aqueous suspension.
8. 8 . The method of claim 7 , wherein the pharmaceutical composition further comprises a diluent or solvent selected from water, Ringer's solution, isotonic sodium chloride solution, oleic acid, and 1,3-butanediol.
9. 9 . The method of claim 7 , wherein the pharmaceutical composition is administered in the form of a liposome.
10. 10 . The method of claim 9 , wherein the liposome comprises phospholipid or phosphatidyl choline.
11. 11 . The method of claim 1 , wherein said composition is adapted for administration by infusion.
12. 12 . The method of claim 1 , wherein said composition is a sterile injectable aqueous solution.
13. 13 . A method of treating hemorrhage in a subject in need thereof, the method comprising administering to the subject an effective amount of nicotinic acid mononucleotide (NaMN) in a sterile injectable aqueous solution by infusion.
14. 14 . A method of treating ulcers in a subject in need thereof, the method comprising administering to the subject an effective amount of a pharmaceutical composition comprising nicotinic acid mononucleotide (NaMN).
15. 15 . The method of claim 14 , wherein the pharmaceutical composition is administered orally.
16. 16 . The method of claim 14 , wherein the NaMN is in crystalline form.
17. 17 . The method of claim 16 , wherein the pharmaceutical composition is formulated as one or more tablets, a troches, a lozenges, a dispersible powder or granules, or hard capsules.
18. 18 . The method of claim 14 , wherein the pharmaceutical composition further comprises GYY4137, sodium hydrosulfide, or pharmaceutically acceptable salts thereof.
19. 19 . The method of claim 14 , wherein the pharmaceutical composition is formulated as an aqueous or oily suspension, an emulsion, a dispersible powder or granules, a syrup or elixir, or one or more tablets, troches, lozenges, or hard or soft capsules.
20. 20 . The method of claim 14 , wherein the pharmaceutical composition is a sterile injectable aqueous suspension, a sterile injectable oleaginous suspension, a sterile injectable aqueous solution, a sterile injectable non-aqueous solution, or a sterile injectable non-aqueous suspension.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of and claims priority to U.S. patent application Ser. No. 16/471,653, filed Jun. 20, 2019, which is a § 371 national phase application of PCT Application No. PCT/AU2017/051435 filed Dec. 21, 2017, which claims priority to Australian Application No. 2016905310 filed Dec. 21, 2016, the entire contents of each of which is incorporated by reference herein. FIELD The invention relates to method of increasing vascular density and/or blood flow in tissue of a subject, to increasing exercise capacity in a subject, and to a composition for increasing vascular density, and blood flow in tissue of a subject, and increasing exercise capacity of a subject. The present application claims priority from Australian provisional application no. 2016905310, the entirety of which is incorporated herein by reference. SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted electronically in XML file format and is hereby incorporated by reference in its entirety. Said XML copy, created on Mar. 27, 2026, is named MBS-02802_SL.xml and is 66,499 bytes in size. BACKGROUND One of the most profound changes to the body as it ages is a decline in the number and function of endothelial cells (ECs) that line the vasculature. According to the Vascular Theory of Aging (Le Couteur and Lakatta, 2010), the progressive loss of vascular density is one of the major causes of aging and age-related diseases, manifesting in diverse ways, including cardiac infarction, stroke, exercise intolerance, erectile dysfunction, liver failure, osteoporosis, impaired wound healing, sarcopenia, dementia and frailty (Askew et al., 2005; Costa and Virag, 2009; Duscha et al., 1999; Kolluru et al., 2012; Lanza and Crea, 2010; McCormick, 1966; Prior et al., 2016). The performance of most organs and tissues is critically dependent on an abundant, fully functional microcapillary network that maintains a supply of oxygen, exchanges heat and various nutrients, and removes the waste products of metabolism. Despite the importance of vascular density loss to human health and longevity, it is surprising how little is understood about its underlying causes. Exercise is currently the best way to delay the effects of aging on the microvasculature by promoting neovascularization in tissues, but almost nothing is known why tissues become desensitized to exercise with age (Bassel-Duby and Olson, 2006; Booth and Thomason, 1991; Hood, 2001). Skeletal muscle is an ideal tissue to study the negative effects of aging on capillary maintenance and neovascularization in response to exercise. In young individuals, muscle performance is critically dependent upon an abundant, fully functional microcapillary network that maintains a supply of oxygen, exchanges heat and various nutrients, and removes the waste products of metabolism. For reasons that are unclear, there is an overall increase in the senescence and apoptosis of muscle endothelial cells with age, leading to blood vessel loss and decreased neovascularization of muscle in response to exercise. The result is reduced muscle mass (sarcopenia) and the steady decline in strength and endurance in the later decades of life, even with exercise. It would therefore be advantageous to increase vascular density and/or blood flow in aged subjects. An increase in vascularisation would also be of benefit in subjects of any age seeking to increase vascular density and/or blood flow in muscle tissue to increase physical performance, or in subjects of any age suffering from conditions where an increase in vascular density and/or blood flow may be of benefit. Despite their potential utility, only a few exercise-mimetic agents have been reported (e.g. resveratrol and PPARγ agonists), none of which are known to work by promoting neovascularization or muscle capillary density. What is needed are methods for increasing vascular density and/or blood flow in tissue of subjects. SUMMARY The inventors have found that increasing Sirtuin 1 (SIRT1) activity or expression in endothelial cells of tissue, e.g. in skeletal muscle, results in an increase in vascular density in that tissue. The inventors have further found that subjects in which endothelial cell SIRT1 activity or expression is increased have increased exercise capacity. Accordingly, a first aspect of the present invention provides a method of increasing vascular density and/or blood flow in tissue of a subject, the method comprising administering to the subject an effective amount of an agent which elevates SIRT1 activity or SIRT1 expression in endothelial cells of the subject. An alternative first aspect provides an agent which elevates SIRT1 activity or SIRT1 expression in endothelial cells for use in increasing vascular density and/or blood flow in tissue of a subject, or use of an agent which elevates SIRT1 activity or SIRT1 expression in endothelial cells in the manufacture of a medica