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WO 2016/114655 Al July 2016 (21.07.2016) 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 2016/114655 Al July 2016 (21.07.2016) W P O PCT (51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, A61K 31/365 (2006.01) A61K 31/5517 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, A61K 31/475 (2006.01) A61P 25/28 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, A61K 31/50 (2006.01) A61K 45/06 (2006.01) HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, (21) International Application Number: MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PCT/NL20 16/050021 PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (22) International Filing Date: SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 12 January 2016 (12.01 .2016) TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (26) Publication Language: English GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, (30) Priority Data: TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, 2014 114 12 January 2015 (12.01.2015) NL TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, 2014 123 13 January 2015 (13.01.2015) NL DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, 2015608 13 October 2015 (13. 10.2015) NL LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, 2015712 3 November 2015 (03. 11.2015) NL SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). (71) Applicant: RY PHARMA B.V. [NL/NL]; Singel 11, 4797 BJ Willemstad (NL). Published: — with international search report (Art. 21(3)) (72) Inventor: TUK, Lambertus; c/o Singel 11, 4797 BJ Willemstad (NL). — before the expiration of the time limit for amending the claims and to be republished in the event of receipt of (74) Agent: JANSEN, CM.; V.O., Carnegieplein 5, 25 17 KJ amendments (Rule 48.2(h)) Den Haag (NL). (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (54) Title: TREATING NEUROMUSCULAR OR NEUROLOGIC DISEASE THROUGH REDUCING GABAERGIC AND/OR GLYCINERGIC INHIBITORY NEUROTRANSMITTER OVERSTIMULATION (57) Abstract: The disclosure provides novel methods of treating neuromuscular or neurologic disease, for example, Amyotrophic lateral sclerosis (ALS), through reducing GABAergic and Glycinergic inhibitory neurotransmitter activity overstimulation. Pharma ceutical compositions comprising one or more compounds capable of reducing Glycinergic activity and/or one or more compounds capable of reducing GABAergic activity are also provided. Methods for treating one or more symptoms caused by inhibitory neuro - transmitter overstimulation (e.g., muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dys phagia, dysarthria, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction and gastrointest inal dysfunction) in an individual afflicted with ALS or an ALS- like disorder are also provided. Title: Treating neuromuscular or neurologic disease through reducing GABAergic and/or Glycinergic inhibitory neurotransmitter overstimulation. FIELD OF THE INVENTION The disclosure provides novel methods of treating neuromuscular or neurologic disease, for example, Amyotrophic lateral sclerosis (ALS), through reducing GABAergic and Glycinergic inhibitory neurotransmitter activity overstimulation. Pharmaceutical compositions comprising one or more compounds capable of reducing Glycinergic activity and/or one or more compounds capable of reducing GABAergic activity are also provided. Methods for treating one or more symptoms caused by inhibitory neurotransmitter overstimulation (e.g., muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, movement difficulties, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction and gastrointestinal dysfunction) in an individual afflicted with ALS or an ALS-like disorder are also provided. BACKGROUND OF THE INVENTION Motor neuron diseases (MNDs) are a group of progressive neurological disorders in which the motor neurons of the patient become dysfunctional. Amyotrophic lateral sclerosis (ALS) is the most common MND and is characterized by progressive muscular weakness and atrophy that is related to motoneuron cell death. The disease generally progresses rapidly and is inevitably fatal with respiratory failure as the relatively uniform cause of death. ALS incidence ranges from 1.5 to 2.5 patients per 100,000 annually, with a lifetime risk of circa 1 in 400 persons. The mean age of onset is circa 60 years, with a median survival of two to four years from symptom onset, although a small percentage of patients lives longer than ten years. ALS is part of a broad spectrum of neurodegenerative indications that are characterized by the progressive degeneration of motoneurons. Other syndromes related to this spectrum of disorders are listed in table 1 under neuromuscular disease among others including Progressive bulbar palsy (PBP), Progressive muscular atrophy (PMA), Primary lateral sclerosis (PLS), Flail arm syndrome (Vulpian- Bernhardt syndrome), Flail leg syndrome, ALS with multi-system involvement such as observed in ALS with frontotemporal dementia (Silani et al. 2011). ALS symptoms overlap with the group of neuromuscular disorders leading to a gradual muscle weakness and to a common set of physical symptoms including difficulty with speech, difficulty with mobility and fine motor skills as listed in table 1, and with the group of muscle diseases listed in table 2. Furthermore it in this disclosure will be concluded that ALS symptoms clinically relevant overlap with the (neurologic) diseases listed in table 3 and 4. Currently there is no effective treatment available for ALS or ALS like disease. Riluzole (Rilutek®) displays minor efficacy in ALS, only prolonging tracheostomy-free survival with three months. Baclofen has been used for the treatment of anti-spastic treatment in ALS patients and is thought to exert its effects through exerting GABAergic action through binding at GABA-B receptors. One of the objects of the invention is to provide improved treatments for ALS and ALS-like disorders as listed in tables 1, 2, 3 and 4. SUMMARY OF THE INVENTION Methods and compositions are provided for treating one or more symptoms caused by inhibitory neurotransmitter overstimulation. Symptoms may include those listed in tables 7 and/or 8, preferably muscle wasting, loss of muscle function, respiratory depression, dysphagia, dysarthria, movement difficulties, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction and gastrointestinal dysfunction, more preferably muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, movement difficulties, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction and gastrointestinal dysfunction. Symptoms may include those listed in tables 7a- 7f, preferably tables 7a- 7d. Methods and compositions are provided for treating ALS and ALS-like disorders, such those listed in tables 1, 2, 3 and 4, preferably for the treatment of ALS. As demonstrated in the examples, these disorders exhibit symptoms which hererin are concluded to be caused by inhibitory neurotransmitter overstimulation. The methods comprise decreasing GABAergic and/or Glycinergic inhibitory activity in an individual in need thereof, preferably using compounds disclosed in Tables 5 and/or 6. The methods result in an overall (or net) decrease in GABAergic and/or Glycinergic activity. Preferred embodiments are summarized as follows. 1. A method for treating one or more symptoms caused by inhibitory neurotransmitter overstimulation (e.g., one or more symptoms selected from tables 7 and/or 8, preferably those listed in tables 7a- 7f, more preferably tables 7a- 7d, most preferably muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction and gastrointestinal dysfunction) in an individual afflicted with ALS or an ALS-like disorder, the method comprising decreasing GABAergic and/or Glycinergic inhibitory activity in an individual in need thereof. Preferably glycinergic activity is decreased by administrating a therapeutically effective amount of a compound that modulates the glycine receptor or that leads to an increase in efficacy of compounds that (at least partly) exert their action through the glycine receptor thereby causing the reduction of Glycinergic activity, or that increase the availability of compounds that (at least partly) exert their action through the glycine receptor thereby causing the reduction of Glycinergic activity. Preferably, GABAergic activity is reduced by the systemic administration of a therapeutically effective amount of a GABA receptor inhibitor and / or a compound that leads to an increase in availability or efficacy of compounds that exert their action (at least partly) through the GABA receptor causing the reduction of net GABAergic activity. 2. A method for treating one
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