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WO 2016/054475 Al 7 April 2016 (07.04.2016) P O P C T

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WO 2016/054475 Al 7 April 2016 (07.04.2016) P O P C T (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 2016/054475 Al 7 April 2016 (07.04.2016) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A01N 47/46 (2006.01) A61P 25/08 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 31/26 (2006.01) A61P 25/28 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (21) International Application Number: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/US2015/053657 HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (22) International Filing Date: KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, 2 October 2015 (02. 10.2015) 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, (25) Filing Language: English SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (26) Publication Language: English TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 62/059,594 3 October 2014 (03. 10.2014) US kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, (71) Applicant: THE JOHNS HOPKINS UNIVERSITY TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, [US/US]; 3400 N . Charles St., Baltimore, Maryland 21218 TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (US). DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, (72) Inventors: TALALAY, Paul; 55 12 BoxhiU Ln, Baltimore, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Maryland 212 10 (US). ZIMMERMAN, Andrew; 38 GW, KM, ML, MR, NE, SN, TD, TG). Daniels St., Hopedale, Massachusetts 01747 (US). Published: (74) Agent: MCGOWAN, Malcolm; Cermak Nakajima & McGowan LLP, 127 S. Peyton St., Suite 200, Alexandria, — with international search report (Art. 21(3)) Virginia 223 14 (US). (54) Title: COMPOSITIONS AND METHODS FOR TREATING AUTISM SPECTRUM DISORDERS (57) Abstract: The instant disclosure features, among other Fig. 4 things, compositions and methods for treating an autism spectrum disorder in a human. The compositions comprise an effective amount of: (1) an isothiocyanate (e.g., sulforaphane or a derivative thereof) or (2) a glucosinolate, and optionally, an enzyme, to thereby treat an autism spec trum disorder and/or reduce the severity of at least one symptom of the disorder. Methods for preparing such com positions are also featured. © weeks weeks v o o COMPOSITIONS AND M ETHODS FOR TREATING AUTISM SPECTRUM DISORDERS Background [001] Autism Spectru m Disorder (ASD) encompasses a group of com plex disorders of brain development. These disorders are cha racterized, in varying degrees, by difficulties in socia l interaction, verba l and nonverba l com munication and repetitive behaviors. These disorders include, but are not li mited to, autistic disorder, childhood disintegrative disorder, pervasive developmental disorder-not otherwise specified (PDD-NOS), and Asperger syndrome. ASD affects 1-2% of predomina ntly male individua ls. ASD is an enormous medical and economic problem in the United States and, at present, there is no approved, mechanism-based treatment. Summary [002] The disclosure is based, at least in part, on the resu lts from a clinical study demonstrating that patients with moderate t o severe autism exhibited marked improvements in aberra nt behavior and verba l com munication following treatment with sulfora phane. In fact, on subsca le analysis of Clinica l Globa l Impression-I mprovement (CG I-I) scale scores after treatment with sulforapha ne, 46%, 54%, and 42% of su lfora pha ne reci pients were much or very-m uch improved on social interaction, aberra nt behavior, and verba l com munication, respectively, as com pared t o 0%, 9%, and 0%, respectively, for placebo recipients. These studies indicate that com positions com prising an isothiocyanate (e.g., sulforapha ne or derivatives of sulfora pha ne) possessing sulforapha ne activity, are useful for treating autism spectrum disorders in humans. [003] Accordingly, in one aspect, the disclosure featu res a method for treati ng an autism spectru m disorder in a huma n. The method com prises ad ministering to the huma n an effective amount of an isothiocya nate, such as su lforapha ne or a derivative thereof, to thereby treat the disorder. [004] In another aspect, the disclosu re featu res a method for treating an autism spectru m disorder in a huma n. The method com prises administering t o the huma n an effective amount of an isothiocya nate (e. g., sulfora phane or a derivative thereof) to thereby treat the disorder, wherei n the huma n has not experienced a seizure within one yea r prior to administering the sulforapha ne or derivative thereof. [005] In yet another aspect, the disclosure featu res a method for treating an autism spectru m disorder in a huma n, which method com prises admi nistering t o the human : (a) an effective amount of an isothiocya nate (e. g., su lfora pha ne or a derivative thereof) t o thereby treat the disorder; and (b) an effective amount of an anti-seizure drug. [006] In another aspect, the disclosu re featu res a method for treating an autism spectru m disorder in a huma n, the method com prisi ng ad ministeri ng t o the huma n an effective amou nt of an isothiocya nate (e.g., sulfora pha ne or a derivative thereof) t o thereby treat the disorder, wherein the huma n is not concu rrently bei ng treated with a drug associated with increased risk of seizure. [007] In another aspect, the disclosu re featu res a method for treating an autism spectrum disorder, which method com prises: (i) ad ministeri ng t o the huma n an effective amou nt of an isothiocya nate (e. g., sulfora pha ne or a derivative thereof) t o thereby treat the disorder; and (ii) monitoring the huma n for the occurrence of seizures. [008] In another aspect, the disclosu re featu res a method for treating an autism spectru m disorder in a huma n, the method com prising administering t o the huma n an effective amou nt of an isothiocya nate (e. g., sulfora pha ne or a derivative thereof) t o thereby treat the disorder, wherei n the isothiocya nate (e. g., the sulfora pha ne or derivative thereof) is t o be ad ministered in conjunction with a reduced ca lorie diet. [009] In some embodiments of any of the methods descri bed herein, the autism spectru m disorder is autistic disorder, chi ld hood disintegrative disorder, pervasive developmenta l disorder-not otherwise specified (PDD-N OS), or Asperger syndrome. [0010] In some embodiments of any of the methods described herein, the effective amount of an isothiocya nate (e.g., sulforapha ne or a derivative thereof) can be, e.g., between 25 and 75 µιηοΙ if the huma n weighs 100 pounds or less; between 75 and 125 µιηοΙ if the human weighs between 101 t o 199 pounds; or between 125 and 175 µιηοΙ if the human weighs more tha n 200 pounds. The effective amount can be administered daily. In some embodiments, the effective amount of an isothiocyanate (e.g., sulfora phane or a derivative thereof) ca n be 50 µιηοΙ, if the human weighs 100 pounds or less; between 100 µιηοΙ if the human weighs between 101-199 pounds; or 150 µιηοΙ if the huma n weighs more than 200 pounds. In some embodiments, the effective amount is 5 t o 15 mg, 15 t o 25 mg, 20 t o 30 mg, or 5 t o 50 mg, e.g., daily. In some embodiments, the effective amou nt (e.g., the effective daily amou nt) is 5 t o 15 mg if the human weighs less tha n 100 pounds; 15 t o 25 mg if the human weighs between 101 and 199 pou nds, or 20 t o 35 mg if the huma n weighs more tha n 200 pounds. In some embodi ments, the effective amount is 4 t o 12.5 mg, 9 t o 25 mg, 12.5 t o 38 mg, or 3 to 45 mg, e.g., daily. In some embodiments, the effective amou nt (e.g., the effective daily amount) is 4 t o 12.5 mg if the huma n weighs less tha n 100 pounds; 9 t o 25 mg if the huma n weighs between 101 and 199 pounds, or 12.5 t o 38 mg if the human weighs more tha n 200 pounds. [0011] In some embodiments of any of the methods herei n, the effective amou nt is sufficient t o produce at least a 30 (e. g., at least a 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, o r 90) % decrease in tota l Aberrant Behavior Checklist (ABC) and/or Socia l Responsiveness Sca le (SRS) scores (see worki ng exam ples) for a huma n with ASD relative t o the score(s) prior t o treatment with the effective amount of sulfora pha ne or derivative thereof.
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