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WO 2014/076235 Al 22 May 2014 (22.05.2014) P O P C T

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(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 2014/076235 Al 22 May 2014 (22.05.2014) P O P C T (51) International Patent Classification: (74) Agent: ICOSA; 83 avenue Denfert-Rochereau, F-75014 A61K 31/00 (2006.01) A61K 38/11 (2006.01) Paris (FR). A61K 31/196 (2006.01) A61P 25/28 (2006.01) (81) Designated States (unless otherwise indicated, for every A61K 31/7088 (2006.01) A61P 25/00 (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/EP2013/073942 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, 15 November 2013 (15.1 1.2013) KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, (25) Filing Language: English MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (26) Publication Language: English SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, (30) Priority Data: TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, 12193087.9 16 November 2012 (16. 11.2012) EP ZW. 61/727,235 16 November 2012 (16. 11.2012) US (84) Designated States (unless otherwise indicated, for every (71) Applicants: NEUROCHLORE [FR/FR]; INMED, Pare kind of regional protection available): ARIPO (BW, GH, Scientifique de Luminy, F-13273 Marseille Cedex 09 (FR). GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, INSERM (INSTITUT NATIONAL DE LA SANTE ET UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, DE LA RECHERCHE MEDICALE) [FR/FR]; 101 rue TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, ΓΓ de Tolbiac, F-75654 Paris Cedex 13 (FR). UNIVERSITE EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, , LT, LU, LV, AIX MARSEILLE [FR/FR]; 58 boulevard Charles Livon, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, Marseille 7, F-13284 Marseille Cedex 7 (FR). CENTRE HOSPITALIER UNFVERSITAIRE DE BREST KM, ML, MR, NE, SN, TD, TG). [FR/FR]; 2 avenue Foch, F-29609 Brest Cedex (FR). Declarations under Rule 4.17 : (72) Inventors: BEN-ARI, Yehezkel; Villa Arbousset, 969 — of inventorship (Rule 4.17(iv)) chemin du Baguier, F-13600 La Ciotat (FR). LEMONNI- Published: ER, Eric; 13 rue Monseigneur Graveran, F-29200 Brest (FR). BURNASHEV, Nail; 34 rue Nicole Zemmour, Bati- — with international search report (Art. 21(3)) ment A, F-13009 Marseille (FR). TYZIO, Roman; — before the expiration of the time limit for amending the Meteore Batiment B, 159 boulevard Michelet, F-13009 claims and to be republished in the event of receipt of Marseille (FR). amendments (Rule 48.2(h)) o o (54) Title: MODULATORS OF INTRACELLULAR CHLORIDE CONCENTRATION FOR TREATING FRAGILE X SYN DROME (57) Abstract: The present invention relates to a composition for treating Fragile X syndrome in a subject in need thereof, wherein said composition comprises an effective amount of a modulator of a chloride transporter. MODULATORS OF INTRACELLULAR CHLORIDE CONCENTRATION FOR TREATING FRAGILE X SYNDROME FIELD OF INVENTION The present invention relates to the treatment of Fragile X syndrome. More specifically, the present invention relates to a method for treating Fragile X syndrome in a subject in need thereof, wherein said method comprises modulating the intracellular level of chloride, such as, for example, by administering to the subject a modulator of a chloride transporter. BACKGROUND OF INVENTION Fragile X syndrome is the most common inherited form of mental retardation, affecting about 1 in every 4000 boys and about 1 in every 8000 girls. Fragile X syndrome (FXS) is a genetic disorder caused by the expansion of a CGG trinucleotide repeat in the 5' untranslated region (5'-UTR) of the Fragile X mental retardation 1 (FMRl) gene, which is located on the X chromosome. The mutation results in a reduced or absent expression of the Fragile X mental retardation protein (FRMP). Even if the exact function of FRMP is not known, experimental evidences have shown that its normal expression is required for normal neural development. Depending at least in part on the length of the CGG repeat expansion, FXS patients will present various degrees of symptoms severity. Major symptoms associated with FXS are mental retardation and learning disabilities, in particular delays in learning how to sit, walk and talk. As a consequence, FXS patients usually present nervous or cluttered speech. Moreover, FXS patients may have deficient central executive, working, phonological and/or visual-spatial memories; or difficulty with face encoding. Behavioral and emotional problems may also be encountered, such as, for example, hyperactivity, stereotypy, anxiety, seizures, impaired social behavior, cognitive delay, irritability, aggression or self-injurious behavior. Moreover, FXS may also cause ophthalmologic problems including strabismus, and recurrent otitis media and sinusitis during early childhood. Due to the high prevalence of Fragile X syndrome, there is a real need for a specific treatment. The patent application EP 2 433 635 describes the use of PAK (p21-activated kinases) modulators for treating Fragile X syndrome. The patent application WO20 12/0 19990 describes the use of glutamate 5 receptor (mGlu5) antagonists for the treatment of Fragile X syndrome. The patent application AU 2011 236093 describes the use of a gamma-aminobutyric acid agonist, in particular of Baclofen, for treating Fragile X syndrome. The drug STX209, a baclofen derivative, is currently under clinical trial for determining its efficacy, safety, and tolerability for the treatment of social withdrawal in adolescents and adults with Fragile X syndrome. Other clinical trials are currently in progress, such as, for example, with AFQ056 (a mGluR5 antagonist developed by Novartis), minocycline hydrochloride (an antibiotic which may lower matrix metalloproteinase 9 (MMP9) levels) or Acamprosate (an agonist of a GABA receptor). However, to the Applicant knowledge, there is currently no drug treatment with prove efficacy for Fragile X syndrome. The Applicant surprisingly showed that the intracellular chloride level was significantly increased in a mouse model of FXS as compared to the wild-type situation, leading to an abnormal neuronal activity (see Examples). This was surprising as Adusei et al (2010 Neuropharmacology 59:167-171) disclose that the chloride transporters NKCCl and KCC2 are not involved in FXS. The present invention thus relates to the use of a modulator of intracellular chloride levels, in particular inhibitor of NKCC or activator of KCC, for treating FXS in a subject in need thereof. SUMMARY The present invention thus relates to a composition for treating Fragile X syndrome in a subject in need thereof, wherein said composition comprises an effective amount of a modulator of a chloride transporter. In one embodiment, said modulator of chloride transporter is not valproic acid, oxytocin, bendroflumethiazide, benzthiazide, buthiazide, chlorothiazide, cyclothiazide, epithiazide, metalthiazide, hydrochlorothiazide, hydro-flumethiazide, methylclothiazide, polythiazide, trichlormethiazide, chlorthalidone, indapamide, metolazone and quinethazone. In one embodiment of the invention, said modulator is an inhibitor of a transporter involved in the importation of chloride into neurons or an activator of a transporter involved in the outflow of chloride from neurons. In one embodiment, said inhibitor is an inhibitor of the expression of a transporter involved in the importation of chloride into neurons, preferably is siRNAs, shRNAs, antisense oligonucleotide, ribozymes or aptamers of a chloride transporter involved in the importation of chloride into neurons. In another embodiment, said inhibitor is an inhibitor of the activity of a transporter involved in the importation of chloride into neurons. In one embodiment, said transporter involved in the importation of chloride into neurons is NKCC, preferably NKCC1. In one embodiment, the inhibitor of NKCC is selected from the group comprising bumetanide, furosemide, ethacrynic acid, torsemide, azosemide, muzolimine, piretanide, tripamide and the like; thiazide and thiazide-like diuretics, such as bendroflumethiazide, benzthiazide, chlorothiazide, hydrochlorothiazide, hydro flumethiazide, methylclothiazide, polythiazide, trichlormethiazide, chlorthalidone, indapamide, metolazone and quinethazone; analogs, functional derivatives and/or prodrugs thereof. In another embodiment, said activator is an activator of the expression of the activity of a transporter involved in the outflow of chloride from neurons. In one embodiment, said transporter involved in the outflow of chloride from neurons is KCC, preferably KCC2. In one embodiment, the effective amount ranges from about 0.01 mg to about 500 mg. In one embodiment, the composition is administered to the subject in need thereof by subcutaneous, intramuscular, intravenous, intraocular, transdermal, topical, parenteral, intranasal and oral administration, or injection. In one embodiment, the subject presents a number of CGG repeats in the 5'-UTR of FMR1 of at least 55, preferably of at least 200. In another embodiment, the subject is diagnosed with Fragile X syndrome. In still another embodiment, the subject is at risk of developing Fragile X syndrome. In one embodiment, the subject is a fetus and the composition is administered to his/her mother. DEFINITIONS In the present invention, the following terms have the following meanings: "Fragile X syndrome" refers to a genetic disease associated with and/or caused by to a defect of the expression of the FMR1 gene and/or of the activity of the FMR1- encoded protein, FMRP. In one embodiment, Fragile X syndrome refers to a condition wherein the FMR1 gene comprises at least 55 CGG repeats in the 5'-UTR.
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  • Azosemide Is More Potent Than Bumetanide and Various Other Loop

    Azosemide Is More Potent Than Bumetanide and Various Other Loop

    www.nature.com/scientificreports OPEN Azosemide is more potent than bumetanide and various other loop diuretics to inhibit the sodium- Received: 21 November 2017 Accepted: 14 June 2018 potassium-chloride-cotransporter Published: xx xx xxxx human variants hNKCC1A and hNKCC1B Philip Hampel 1,2, Kerstin Römermann1, Nanna MacAulay 3 & Wolfgang Löscher1,2 The Na+–K+–2Cl− cotransporter NKCC1 plays a role in neuronal Cl− homeostasis secretion and represents a target for brain pathologies with altered NKCC1 function. Two main variants of NKCC1 have been identifed: a full-length NKCC1 transcript (NKCC1A) and a shorter splice variant (NKCC1B) that is particularly enriched in the brain. The loop diuretic bumetanide is often used to inhibit NKCC1 in brain disorders, but only poorly crosses the blood-brain barrier. We determined the sensitivity of the two human NKCC1 splice variants to bumetanide and various other chemically diverse loop diuretics, using the Xenopus oocyte heterologous expression system. Azosemide was the most potent NKCC1 inhibitor (IC50s 0.246 µM for hNKCC1A and 0.197 µM for NKCC1B), being about 4-times more potent than bumetanide. Structurally, a carboxylic group as in bumetanide was not a prerequisite for potent NKCC1 inhibition, whereas loop diuretics without a sulfonamide group were less potent. None of the drugs tested were selective for hNKCC1B vs. hNKCC1A, indicating that loop diuretics are not a useful starting point to design NKCC1B-specifc compounds. Azosemide was found to exert an unexpectedly potent inhibitory efect and as a non-acidic compound, it is more likely to cross the blood-brain barrier than bumetanide. Te Na+–K+–2Cl− cotransporter NKCC1 (encoded by SLC12A2) plays an important role in Cl- uptake in neu- rons both in developing brain and in adult sensory neurons1,2.