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WO 2015/070280 Al O (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2015/070280 Al May 2015 (21.05.2015) W P O P CT (51) International Patent Classification: (74) Agent: GRIFFITH HACK; GPO Box 4164, Sydney, New A61K 8/18 (2006.01) A61P 39/06 (2006.01) South Wales 2001 (AU). A61K 31/366 (2006.01) A61P 17/18 (2006.01) (81) Designated States (unless otherwise indicated, for every A61K 8/35 (2006.01) kind of national protection available): AE, AG, AL, AM, (21) International Application Number: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, PCT/AU2014/001048 BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, 14 November 2014 (14.1 1.2014) KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, (25) Filing Language: English MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (26) Publication Language: English SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (30) Priority Data: TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. 2013904415 14 November 2013 (14. 11.2013) AU (84) Designated States (unless otherwise indicated, for every (71) Applicant: NEWSOUTH INNOVATIONS PTY LIM¬ kind of regional protection available): ARIPO (BW, GH, ITED [AU/AU]; Rupert Myers Building, Gate 14, Barker GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, Street, UNSW, Sydney, New South Wales 2052 (AU). TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (72) Inventors: WU, Lindsay Edward; 53 1/2 Allen Street, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, Waterloo, New South Wales 2017 (AU). SINCLAIR, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, David Andrew; 43 Newbrook Circle, Chestnut Hill, Mas SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, sachusetts 02467 (US). GW, KM, ML, MR, NE, SN, TD, TG). [Continued on nextpage] (54) Title: SENESCENCE AND SENESCENCE ASSOCIATED SECRETORY PHENOTYPE Flg ri Ce l cycle markers o 00 o © (57) Abstract: The present invention relates to a method of treating or preventing DNA damage in a cell or cellular senescence of a o cell or induction of the senescence associated secretory phenotype (SASP) in a cell, or for treating or preventing the effects of aging, or for preventing or treating cellular senescence and/or induction of SASP associated with high caloric intake or obesity, or for redu - cing the side effects of chemotherapy, radiotherapy, corticoid treatment, anti-retroviral treatment, or PPARy agonist treatment, com - prising administering an effective amount of an NAD+ agonist. WO 2015/070280 Al llll II II 11III II Published: SENESCENCE AND SENESCENCE ASSOCIATED SECRETORY PHENOTYPE Field of the Invention The invention relates to methods of treating or preventing DNA damage and/or cellular senescence, and to methods of treating and preventing conditions associated with DNA damage and/or cellular senescence . Background Cellular senescence is the disruption of cell proliferation and function. During cellular senescence, there is a loss of the ability of the cell to proliferate, although the cell continues to remain viable and metabolically active. Many cell types undergo cellular senescence following a large number of cycles of cell division. For example, when grown in culture, primary cells undergo cellular senescence after approximately 5 0 cell divisions. This barrier to further proliferation following many cycles of cell division has been termed replicative senescence. Replicative senescence is thought to be due to shortening of the cell's telomeres with each successive cell division, causing cells to reach a point (their so-called "Hayflick limit") at which a DNA damage response is triggered, leading ultimately to induction of proliferation arrest and cellular senescence . Cellular senescence can also be induced in the absence of telomere loss or dysfunction. This type of cellular senescence, termed premature senescence, may result from, for example, DNA damage arising from chemotherapy, radiotherapy, or exposure to DNA damaging compounds or stimuli such as sunlight, UV light, and radiation. DNA damage may take the form of chromosomal dysfunction such as aneuploidy arising from unequal chromosome segregation during mitosis, DNA strand breaks, or chemical modification of DNA (e.g. alkylation) . Cellular senescence may also be induced by a DNA damage response (DDR) which may or may not reflect actual DNA damage. Cellular senescence is characterized by, and may be induced by, changes in chromatin organization that induce changes in gene expression, such as for example, the "senescence-associated secretory phenotype ("SASP") in which senescent cells secrete inflammatory cytokines and mitokines that can damage or alter the surrounding tissue. Studies have indicated that cellular senescence is associated with age-related conditions, including thinning of the epidermis, skin wrinkling, hair loss and greying hair, reduction in muscle thickness and muscle strength, increased incidence of inflammation, metabolic disturbances, loss of endurance, and age-associated diseases. In addition, cellular senescence is believed to contribute to damage to healthy tissues experienced during and following chemotherapy and/or radiotherapy, and the poor health effects post chemotherapy and/or radiotherapy. Accordingly, preventing cells from undergoing cellular senescence, or preventing DNA damage, DNA damage response pathways or chromatin changes that would activate senescence, or reversing cellular senescence in cells which have undergone cellular senescence, would be advantageous to prevent or treat age and side effects of cancer treatments. Similarly, preventing cells from undergoing DNA damage and/or senescence in response to exposure to sunlight or exposure to DNA damaging chemicals may reduce skin aging, prevent skin cancer and improve cosmetic appearance. Summary A first aspect provides a method of treating or preventing DNA damage in a cell or cellular senescence of a cell or induction of the senescence associated secretory phenotype (SASP) in a cell, comprising contacting the cell with an NAD + agonist. A second aspect provides a method of treating or preventing DNA damage or cellular senescence or induction of SASP in cells of a subject in need thereof, comprising administering to the subject an effective amount of an NAD + agonist. Alternatively, the second aspect provides use of an NAD + agonist in the manufacture of a medicament for treating or preventing DNA damage or cellular senescence or induction of SASP in cells of a subject in need thereof, or an NAD + agonist for use in treating or preventing DNA damage or cellular senescence or induction of SASP in cells of a subject in need thereof. A third aspect provides a method of reducing the side effects of chemotherapy and/or radiotherapy in a subject in need thereof, comprising administering to the subject an effective amount of an NAD+ agonist. Alternatively, a third aspect provides use of an NAD+ agonist in the manufacture of a medicament for reducing the side effects of chemotherapy and/or radiotherapy in a subject in need thereof, or an NAD+ agonist for use in reducing the side effects of chemotherapy and/or radiotherapy in a subject in need thereof. A fourth aspect provide a method of treating or preventing the effects of aging in a subject in need thereof, comprising administering to the subject an effective amount of an NAD+ agonist. Alternatively, the fourth aspect provides use of an NAD + agonist in the manufacture of a medicament for treating or preventing the effects of aging in a subject in need thereof, or an NAD+ agonist for use in treating or preventing the effects of aging in a subject in need thereof. A fifth aspect provides a method of reducing the side effects of corticoids in a subject in need thereof, comprising administering to the subject an effective amount of an NAD+ agonist. Alternatively, a fifth aspect provides use of an NAD+ agonist in the manufacture of a medicament for reducing the side effects of corticoids in a subject in need thereof, or an NAD+ agonist for use in reducing the side effects of corticoids in a subject in need thereof . A sixth aspect provides a method of reducing the side effects of anti-retroviral treatment in a subject in need thereof, comprising administering to the subject an effective amount of an NAD+ agonist. Alternatively, a sixth aspect provides use of an NAD+ agonist in the manufacture of a medicament for reducing the side effects of anti-retroviral therapy in a subject in need thereof, or an NAD + agonist for use in reducing the side effects of anti-retroviral therapy in a subject in need thereof. A seventh aspect provides a method of reducing the side effects of, or treating or preventing cellular senescence or preventing induction of SASP associated with, PPARy agonists in a subject in need thereof, comprising administering to the subject an effective amount of an NAD + agonist. Alternatively, a sixth aspect provides use of an NAD + agonist in the manufacture of a medicament for reducing the side effects of, or treating or preventing cellular senescence or induction of SASP associated with, PPARy agonists in a subject in need thereof, or an NAD + agonist for use in reducing the side effects of, or treating or preventing cellular senescence or induction of SASP associated with, PPARy agonists in a subject in need thereof. A seventh aspect provides a method of treating or preventing cellular senescence or induction of SASP associated with increased caloric intake and obesity in a subject in need thereof, comprising administering to the subject an effective amount of an NAD + agonist.
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