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WO 2017/210540 Al 07 December 2017 (07.12.2017) W ! P O PCT

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WO 2017/210540 Al 07 December 2017 (07.12.2017) W ! P O PCT (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 2017/210540 Al 07 December 2017 (07.12.2017) W ! P O PCT (51) International Patent Classification: LEIBEL, Rudolph, L.; 464 Riverside Dr. # 1, New York, A61K 31/221 (2006.01) A61K 31/198 (2006.01) NY 10027 (US). COTTER, Sara; 1634 Walnut Avenue, A23L 1/302 (2006.01) Wilmette, IL 60091 (US). (21) International Application Number: (74) Agent: DAVITZ, Michael, A. et al; Leason Ellis LLP, One PCT/US2017/035655 Barker Avenue, Fifth Floor, White Plains, NY 10601 (US). (22) International Filing Date: (81) Designated States (unless otherwise indicated, for every 02 June 2017 (02.06.2017) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, (25) Filing Language: English CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, (26) Publication Language: English DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KH, KN, KP, KR, (30) Priority Data: KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, 62/345,133 03 June 2016 (03.06.2016) MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, 62/375,662 16 August 2016 (16.08.2016) PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (71) Applicants: THE TRUSTEES OF COLUMBIA SD, SE, SG, SK, SL, SM, ST, SV, SY,TH, TJ, TM, TN, TR, UNIVERSITY IN THE CITY OF NEW YORK TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. [US/US]; 412 Low Memorial Library, 535 West 116th (84) Designated States (unless otherwise indicated, for every Street, New York, NY 10027 (US). LEVO THERA¬ kind of regional protection available): ARIPO (BW, GH, PEUTICS, INC. [US/US]; 1701 E. Lake Avenue, Suite GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, 260, Glenview, IL 60025 (US). UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, (72) Inventors: BURNETT, Lisa, Cole; 1380 Riverside Drive TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, Apt. 8E, New York, NY 10033 (US). EGLI, Dieter; 116 EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, Pinehurst Avenue, Apt. R43, New York, NY 10033 (US). MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, (54) Title: METHODS OF TREATING PRADER-WILLI SYNDROME Rationale for treatment in PWS individuals with agents that increase cA P levels and block its degradation o o FIG. 2 (57) Abstract: The present invention relates to methods for regulating prohormone convertase (PCI ) and compounds and treatments which increase PCI levels, for treating Prader-Willi Syndrome (PWS). O [Continued on nextpage] WO 2017/210540 Al llll II II 11III I II I II I III I II II III II I II TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). Published: METHODS OF TREATING A - SYNDROME CROSS-REFERENCE TO RELATED APPLICATIONS The present application claims priority t U.S. Provisional Patent Application No. 62/345,133 filed me 20 ; U.S. Provisional Application No. 62/375,662 filed A g s 16, 2 6, each of which is incorporated by reference ts entirety. GOVERNMENT SUPPORT This work was supported in pa t b grant from th National Institute of Health R ID . 524 con equently, the U.S may have certain rights in the present invention. FIELD OF THE INVENTION The present invention relates to methods for regulating prohormone convertase (PCI) a compounds and treatments which increase PC levels BACKGROUND O F THE INVENTION Prader-Willi syndrome (PWS) is caused by a oss of paternally expressed ge es in an imprinted region of chromosome 15q. Among the canonical pnenotypes are ! p rphagic obesity, central hypogonadism and low growth hormone. Rare niicrodeletion PWS patients define a 9 1 fo minimum critical deletion region encompassing 3 genes, including the non- coding D 6. We have found that N .L 2 a d PC are d wnregu a ed in PWS iPSC- derived neurons as compared t unaffected controls. Nhlh2 and csk transcript levels are reduced so hypothalami of fasted Snordl s" mice. Deficiency of lh in m ce causes obesity, hypogonadism, and growth failure. Nhlh2 promotes expression of the prohormone convertase, (PCI). Hu an and mice deficient in PC display hyperphagic obesity, hypogonadism, decreased growth hormone, and diabetes du to impaired prohormone processing. For example, S r ( " * mice display in vivo functional defect in prohormone processing of proins m . proGf H, and p ghre in associated with reductions in PCI. Currently there are no treatments for PWS patients and effective treatments and mode systems are urgently needed. SUMMARY OF THE INVENTION The methods of the present invention provide for regulating prohormone converiase by administering art effective amount of a phosphodiesterase inhibitor (P.DE4 inhibitor or PDB4i). Expression of the prohormone convettase may be pregu a ed by administration of a therapeutically e ve amount o a PDE4 inhibitor. The P E inhibitor a be administered to cell or to patient w h Prader-Willi syndrome. The PDE4 inhib or may he administered to an obese subject t is also expected that these methods will be se& for treating patients with Schaaf-Yang Syndrome and Autism Spectrum Disorder. The PDE4 inhibitor ay be administered orally, intravenously, subc aneo s y intrathecaliy, topically, intrauasaily, or to the lungs. The P E4 inhibitor can include, theophylline, roflumilast, apreinilast, ibdulast, GSK35627S, M 52, BMX as well as combinations of these drags. n certain embodiments, th P >E4 inhibitor can include any of the inhibitors from Tables 1A or Table IB. In additional embodiments, combinations of P E4 inhibitors ma be used n the present methods. The methods of the present invention also include administering a therapeutically effective amount of a adenylate cyclase activator. The aden ate -cyclase activator can be administered to a cell or to a patient with Prader-Willi syndrome. The adenylate cyclase activator may be administered to an obese subject. The adenylate cyclase activator can foe administered orally, intravenously, intrathecaliy, intranasaliy, topically, or to the lungs. The adenylate cyclase activator can include, Forsko n F , FD2, FD3, FD4, FD5 ( 4 7) FD6 as well as combinations of these drugs. The FDE4 inhibitor may a so b ad inistere together with the adenylate cyclase activator . The methods of the present invention also include administering a therapeutically effective amount of a MC4R agonist. The MC4R agonist can foe administered to a ceil or to a patient with Prader-Willi syndrome. The MC4R agonist may be administered to an obese subject. The M 4 agonist can be adnn'nistered orally, intravenously, in iheca y mtranasally, topically, o to the lungs. The MC4 agonist ca include 4 (Setmelanotide), TTP25 , 2 a inothia o e derivatives, M 493. id combinations thereof. The MC4 agonist can be administered in combination with the PDE4 inhibitors and/or adenylate cyclase activators described herein. The methods of the present invention also include methods wherein the administration results in one or more of the following improvements in the patient: decreases or ameliorates hyperphagia; increases FCSK1 levels; increases PC level and/or activity; decreases circulating proinsulin t insulin ratio, thus increasing insulin secretion; decreases circulating proghrelin t ghre in ratio; decreases circulating PO C to ACT ratio; amelioration of hypothyroidism, decreases circulating ratio of pro-oxytocin to oxytocin, thus increasing oxytocin production in the brain and increases al ha~MSH production in the brain; decreases circulating raiio of pro-BDNF to BDNF (increase brain levels of BDNF); and mcreases the ratio of prohormone: hormone (decreases pro-mature hormone); wherein the symptom, levels, or ratios are in reference to the patient's disease symptom, levels, or ratios. In certain embodiments, the methods pr ide for treating Prader-W Syndrome (PWS) comprising administering a phosphodiesterase 4 inhibitor (POE4i) io a subject in need thereof, thereby alleviating, eliminating or preventing one or more symptoms of PWS. In certain embodiments, administering the P E4i upregulates cyclic adenosine monophosphate (cAMP) concentrations or activity in the subject. In certain embodiments, PWS is characterized by decreased expression of N L 2. n additional embodiments, decreased expression of N 2 results in. decreased expression of PCSKI . In certain embodiments, increasing concentrations or activity of cAMP upregulates expression sk n additional embodiments, the PDE4i is a selective PDE4I. In additional embodiments, the PDE4i i a non-selective PD 4i In certain embod me s, the selective PDE4i is selected from AN2728, apremilast, cilomilast, diazepam, ibudi s teolin mesembrenone- p e!a ast, ro i ast, rolipram, E60 5 GS 35 2 and M 9 2.. a certain embodiments, he non-selective FDE4i selected from methylated xanthines and derivatives thereof, caffeine, an in phy iin , S-isoboiyi-i-methy!xanihine, paraxanthme, pentoxifylline, theobromine, and theophylline. In yet additional embodiments, the one or more symptoms include hyperphagia, reduced metabolic rate, obesity, hypogonadism, hyp a re na s , decreased growth hormone production, poor muscle tone, sleep disorders, gastrointestinal disorders, reduced stamina, reduced ability to focus, impaired cognition, behavioral disorders, anxiety, growth failure, reduced conversion of immature hormones to mature and active forms, and diabetes i e !itus and diabetes insipidus. In certain embodiments, the method further comprises administering one or more additional therapeutic agents effective for treating or alleviating one or more symptoms of S. In certain embodiments, the immature hormones comprise one or more of insulin, ghreiin, GHRH, alpha-MSH, oxytocin, orexits, BDNF, vasopressin, NPY, AGRP, an gonadotropins, AC'TH.
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