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WO 2017/070647 Al 27 April 2017 (27.04.2017) 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 2017/070647 Al 27 April 2017 (27.04.2017) P O P C T (51) International Patent Classification: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, A61K 31/455 (2006.01) C12N 15/86 (2006.01) KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, A61K 31/465 (2006.01) A61P 27/02 (2006.01) MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, A61K 31/19 (2006.01) A61P 27/06 (2006.01) OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, A61K 48/00 (2006.01) A61K 45/06 (2006.01) SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, (21) International Application Number: ZW. PCT/US2016/058388 (84) Designated States (unless otherwise indicated, for every (22) International Filing Date: kind of regional protection available): ARIPO (BW, GH, 24 October 2016 (24.10.201 6) GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, (25) Filing Language: English TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (26) Publication Language: English DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, (30) Priority Data: LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, 62/245,467 23 October 2015 (23. 10.2015) SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, 62/366,21 1 25 July 2016 (25.07.2016) GW, KM, ML, MR, NE, SN, TD, TG). (71) Applicant: THE JACKSON LABORATORY [US/US]; Declarations under Rule 4.17 : 600 Main Street, Bar Harbor, ME 04609 (US). — as to applicant's entitlement to apply for and be granted a patent (Rule 4.1 7(H)) (72) Inventors: JOHN, Simon, W.M.; 7 Holland Avenue, Bar Harbor, Maine 04609 (US). WILLIAMS, Peter, Alexan¬ — as to the applicant's entitlement to claim the priority of the der; 209 Kelleytown Road, Tremont, Maine 04612 (US). earlier application (Rule 4.1 7(in)) (74) Agents: LU, Yu et al; McCarter & English, LLP, 265 Published: Franklin Street, Boston, MA 021 10 (US). — with international search report (Art. 21(3)) (81) Designated States (unless otherwise indicated, for every — before the expiration of the time limit for amending the kind of national protection available): AE, AG, AL, AM, claims and to be republished in the event of receipt of AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, amendments (Rule 48.2(h)) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, o o (54) Title: NICOTINAMIDE FOR USE IN THE TREATMENT AND PREVENTION OF OCULAR NEURODEGENERATIVE o DISORDER (E.G. GLAUCOMA) (57) Abstract: The invention relates to the use of a pharmaceutical composition containing nicotinamide (NAM) and/or pyruvate as a neuroprotective medicament or gene therapy in the treatment of neurodegenerative disorders, in particular axon degeneration of neuronal tissue in ocular-related neurodegeneration diseases including glaucoma. NICOTINAMIDE FOR USE IN THE TREATMENT AND PREVENTION OF OF OCULAR NEURODEGENERATIVE DISORDER (E.G. GLAUCOMA) STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH The present invention was made with U.S. government support under Grant No. R01 EY01 1721, awarded by the National Institute of Health (NIH). The U.S. government has certain rights in the invention. REFERENCE TO RELATED APPLICATION This application claims the benefit under 35 U.S.C. §119(e) to U.S. Provisional Application Nos. 62/245,467, filed on October 23, 2015, and 62/366,211, filed on July 25, 2016, the entire contents of which are hereby incorporated by reference in their entirety. BACKGROUND OF THE INVENTION Axon injury is an early event in neurodegenerative diseases. Neurodegenerative diseases are characterized by a dysfunction or loss of viable nerve cells from either the peripheral or the central nervous system. In many cases axon degeneration is shown to precede neural loss, which is a process that is invariably more pronounced at the distal rather than the proximal end of axonal processes. Upstream molecular signals that trigger the neurodegeneration cascades in the neuron remain unknown. There are reports suggesting the use of nicotinamide adenine dinucleotide (NAD) and its related compounds to reduce axon degeneration. For example, US 2006-0211744 Al (the '744 application) describes the use of agents, including NAD, NADH, and nicotinamide (NAM), to reduce chronic neural degeneration. Using a cell culture model of transected dorsal root ganglion (DRG) neuron axon, the '744 application discloses that NAD provided a protecting effect to these neuron against axon degeneration. The '744 application further discloses that NAM reduces neural degeneration in mouse model for Experimental Autoimmune Encephalomyelitis (EAE), Amyotrophic Lateral Sclerosis (ALS), and Relapsing Remitting Multiple Sclerosis (RRMS). US Patent No. 7,776,326 (the '326 patent) discloses a method of treating axonal degradation in neuropathic diseases in mammals by administering agents that increases NAD activity in the injured neurons. Using primary cell cultures of dorsal root ganglion (from spinal nerves) and axotomy (mechanical cut) at a location close to soma, the '326 patentees explicitly concluded that nicotinic acid and NAM did not work to diminish axonal degeneration. In an eye injection study, the '326 patentees again stated that, when injected intravitreally, NAM did not show any difference from the control animals. Glaucoma is one of the most common neurodegenerative diseases, and represents the leading cause of irreversible blindness, affecting over 70 million people worldwide (Quigley and Broman, Br J Ophthalmol 90, 262-267, 2006), especially in the elderly. Glaucoma is a complex, multifactorial disease characterized by the progressive dysfunction and loss of retinal ganglion cells (RGCs) leading to vision loss. High intraocular pressure (IOP) and increasing age represent susceptibility factors for neurodegeneration for glaucoma. Recent advances have hinted to a variety of molecular changes occurring in glaucomatous tissues at the early stages of disease (Howell et al., Journal of Clinical Investigation 121, 1429-1444, 201 1; Nickells et al., Annu Rev Neurosci 35, 153-179, 2012). Early cellular and molecular mechanisms that initiate glaucomatous damage within RGCs are poorly known. It appears that the RGCs are insulted at multiple sites very early in glaucoma including changes affecting their cell bodies, dendrites and synapses in the retina as well as their axons in the optic nerve. The mechanism how high IOP and aging drive neuronal vulnerability and initiate glaucoma in humans is still unclear. Although there are available strategies to alleviate elevated IOP, there are no effective treatments or preventive measures targeting ocular neural degeneration. Accordingly, there is a continuing need in deciphering the upstream molecular signals that trigger the initial neurodegenerative process as well as identifying new molecular targets, so as to provide therapeutic interventions for reducing RGC damage in the retina and axon degeneration, particularly in the treatment of glaucoma. SUMMARY OF THE INVENTION The present invention is primarily predicated on our finding that there is potential effect of nicotinamide (NAM) or pyruvate, or a combination thereof, to protect neuronal cell body, axon, and an associated cell type, thus being beneficial to the treatment of neurodegeneration {e.g., axon degeneration) and ocular neurodegeneration diseases {e.g., glaucoma). It is an object of the present invention to provide a method of treating or preventing glaucoma, comprises the step of administering to a subject in need of treatment of a pharmaceutical composition comprising a therapeutic effective amount of NAM and/or pyruvate. It is an object of the present invention to provide a method of lowering intraocular pressure, e.g., in glaucoma, comprises the step of administering to a subject in need of treatment of a pharmaceutical composition comprising a therapeutic effective amount of NAM and/or pyruvate. It is an aspect of the present invention to provide a method of improving visual function in patients having or suffering from glaucoma, comprises the step of administering to a subject in need of treatment of a pharmaceutical composition comprising a therapeutic effective amount of NAM and/or pyruvate. The present therapy treatment (medicaments and/or gene therapy), without being bound by a particular theory, is believed to work by lowering the intraocular pressure by two main mechanisms: 1) reducing aqueous humor production, and/or 2) increasing aqueous humor outflow. The present therapy can serve as an effective treatment by lowering the high IOP, thus preserving the axon such as optic nerve, and preventing the subsequent loss of visual function. The present therapy treatment is useful to treat or prevent neurodegeneration in glaucoma. The present glaucoma treatment is effective in treating or preventing neural dysfunction and neurodegeneration at the level of retina (e.g., RGCs). Glaucoma can exist at any levels of intraocular pressure (high IOP or normal IOP). The present therapy treatment provides an IOP-independent effect of neuroprotective effect on retinal cells such as the retinal ganglionic cells (RGCs). In certain embodiments, the present treatment prevents and/or delays the progression of glaucoma (e.g., primary open angle glaucoma or POAG) via reducing the intraocular pressure. Almost all current strategies for treating glaucoma are aimed at lowering or preventing a rise in IOP. In certain embodiments, the present treatment prevents and/or delays the progression of glaucoma (e.g., primary open angle glaucoma or POAG) via both providing direct neuroprotection and reducing the intraocular pressure.
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  • Small Cell Carcinoma of the Ovary, Hypercalcemic Type (SCCOHT) Beyond SMARCA4 Mutations: a Comprehensive Genomic Analysis

    Small Cell Carcinoma of the Ovary, Hypercalcemic Type (SCCOHT) Beyond SMARCA4 Mutations: a Comprehensive Genomic Analysis

    cells Article Small Cell Carcinoma of the Ovary, Hypercalcemic Type (SCCOHT) beyond SMARCA4 Mutations: A Comprehensive Genomic Analysis Aurélie Auguste 1,Félix Blanc-Durand 2 , Marc Deloger 3 , Audrey Le Formal 1, Rohan Bareja 4,5, David C. Wilkes 4 , Catherine Richon 6,Béatrice Brunn 2, Olivier Caron 6, Mojgan Devouassoux-Shisheboran 7,Sébastien Gouy 2, Philippe Morice 2, Enrica Bentivegna 2, Andrea Sboner 4,5,8, Olivier Elemento 4,8, Mark A. Rubin 9 , Patricia Pautier 2, Catherine Genestie 10, Joanna Cyrta 4,9,11 and Alexandra Leary 1,2,* 1 Medical Oncologist, Gynecology Unit, Lead Translational Research Team, INSERM U981, Gustave Roussy, 94805 Villejuif, France; [email protected] (A.A.); [email protected] (A.L.F.) 2 Gynecological Unit, Department of Medicine, Gustave Roussy, 94805 Villejuif, France; [email protected] (F.B.-D.); [email protected] (B.B.); [email protected] (S.G.); [email protected] (P.M.); [email protected] (E.B.); [email protected] (P.P.) 3 Bioinformatics Core Facility, Gustave Roussy Cancer Center, UMS CNRS 3655/INSERM 23 AMMICA, 94805 Villejuif, France; [email protected] 4 Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY 10001, USA; [email protected] (R.B.); [email protected] (D.C.W.); [email protected] (A.S.); [email protected] (O.E.); [email protected] (J.C.) 5 Institute for Computational Biomedicine, Weill Cornell