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(19) United States (12) Patent Application Publication (10) Pub US 20140349964A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0349964 A1 SHIOTA et al. (43) Pub. Date: NOV. 27, 2014 (54) METHODS FOR INDUCING OREXIN Publication Classi?cation NEURONS AND AGENT FOR TREATING NARCOLEPSY 0R EATING DISORDER (51) Int- Cl A61K 31/7008 (2006.01) (71) Applicant: THE UNIVERSITY OF TOKYO, G01N 33/50 (2006-01) Tokyo (JP) C12Q 1/68 (2006.01) C12N 5/0793 (2006.01) (72) Inventors: Kunio SHIOTA; Tokyo (JP); Shintaro (52) US, Cl, YAGI, Tokyo (JP); Koji HAYAKAWA, CPC ........ .. A61K 31/7008 (2013.01); C12N 5/0619 Tokyo (JP); Mitsuko (2013.01); G01N33/5058 (2013.01); C12Q HIROSAWA-TAKAMORI, Tokyo (JP); 1/6876 (2013.01); CIZN 2506/02 (2013.01); Daisuke ARAI, Tokyo (JP); Keiji C] 2N 2501/999 (201 3 .01); CIZN 2506/08 HIRABAYASHI, TOKYO (JP) (2013.01); CIZQ 2600/]58 (2013.01); CIZQ 2600/]36 (2013.01) (21) App1.No.: 14/224,730 USPC 514/62; 435/377; 536/53; 435/29; 506/10; 435/6.12; 435/6.11; 435/6.13 (22) Flled. Mar. 25, 2014 (57) ABSTRACT Related US Application Data The invention provides a method for producing an orexin _ _ _ _ _ neuron by culturing a pluripotent stem cell or a neural pro (63) commuanon'm'pan Of apphcanon NO' PCT/JP2012/ genitor cell in the presence of N-acetyl-D-mannosamine and 075137, ?led on Sep' 28’ 2012' optionally in the presence of at least one inhibitor selected (60) Provisional application No. 61/540,601; ?led on Sep. from the group 601151“ng Of a Simnn 1 inhibitor and an 29, 2011_ O-linked B-N-acetylglucosamine transferase inhibitor. The invention also provides a therapeutic agent for narcolepsy or (30) Foreign Application Priority Data eating disorders; such as anorexia; containing N-acetyl-D mannosamine; Which is based on the induction of orexin Mar. 25; 2013 (JP) ............................... .. 062298/2013 neuron in vivo. Patent Application Publication Nov. 27, 2014 Sheet 1 0f 9 US 2014/0349964 A1 Mouse ES ceiis . am am day 0 day 4 day 7 day 10 "" ' ‘ ‘ ‘ 1 0.2, 1, 5 mm GicNac, Mamas or NeuEAc was added to medium i _ __ __ .. .. __......;day0-1G v_ m; 1 mm GicNac, ManNac ar NeuSAc was added to meciium ’ Atdifferenttime i am Total ama imm cantmi: Her! ' any: i R”??? ; Patent Application Publication Nov. 27, 2014 Sheet 2 0f 9 US 2014/0349964 A1 Treatment Her; Act?) Rm} ._ day 0 _ day 7 day 13 _ day‘zs Giuccse __ 18?¥¥@__ i _ .5 2%, cancentration ‘ t _ _ 1 mM GEcNac, ManNac, NeuSAc were added from day 7 0f differentiaticn FIG. 4 undifferentiated RT {3;} > .. FIG“ 5 Patent Application Publication Nov. 27, 2014 Sheet 3 0f 9 US 2014/0349964 A1 NSph farmation Differentiation inducticn E145 fetus (6 days) (19 days) endbrain 524.5 19' ?éé? ' ' ‘ fiz‘ggiz *‘if‘iii??i'? §§§§Z§E§ HG, 6 Hart 5 ~ mm; HG, 7 Patent Application Publication Nov. 27, 2014 Sheet 4 0f 9 US 2014/0349964 A1 gmsm i mmmmékpressirm waif? F56. 8 PEG. 9 Patent Application Publication Nov. 27, 2014 Sheet 6 0f 9 US 2014/0349964 A1 Mouse ES ceiis . ?vnixi'i?iiiiiéi WW : iiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiii w I §Mnuse ES ceiis were differentiation cuituredé d?” 0 day * day 7 day 10 For 10 days, ManNAc was added fmm day 0 g 1 mm Manng I inf differentiation, and inhibitors (90527 and; ‘ ' iBADGP} ware added imm day 7 of Human iPS ceiis iiniibwi ............................................. 52% Siiiii day 0 day 7 day 16 day 16, 1 mM ivianNAc - i Mouse ES ceiis were differentiation cuiturecig For50f differentiation, 20 day , ManNAc and was inhibitors added {90527from day and; 0 iBADGP) were added from day 14 ‘ of differentiation Patent Application Publication Nov. 27, 2014 Sheet 7 0f 9 US 2014/0349964 A1 61-week-0Eci (controt) 61_week~oid (ManNac administratian) FEG. ’52 Patent Application Publication Nov. 27, 2014 Sheet 8 0f 9 US 2014/0349964 A1 8'? 6 5H4 é 0 if #2 43 PEG. 12 (Cantinued) Patent Application Publication Nov. 27, 2014 Sheet 9 0f 9 US 2014/0349964 A1 number sf arexin mamas 86 83,3 i N ma 3; m 70 13" 6L» 6}“ week» week week-aid aid aid {ManNAc (minim!) administmiian) HG. 12 (Camimled) US 2014/0349964 A1 Nov. 27, 2014 METHODS FOR INDUCING OREXIN DOCUMENT LIST NEURONS AND AGENT FOR TREATING NARCOLEPSY OR EATING DISORDER Patent Documents [0001] This application is a continuation-in-part applica [0006] [patent document 1] JP-A-HEI10-182685 tion based on PCT/JP2012/075137, and all teachings dis [patent document 2] JP-A-2001-78794 closed wherein are incorporated herein. This application [patent document 3]U.S. Pat. No. 6,274,568 claims priority to a patent application No. 2013-062298 ?led [patent document 4] WO2010/027028 in Japan on Mar. 25, 2013. [patent document 5] JP-A-2011-178702 TECHNICAL FIELD OF THE INVENTION Non-Patent Documents [0002] The present invention relates to a method for induc [0007] [non-patent document 1] Pharmacological Reviews ing an orexin neuron, more particularly, a method for ef? 61:162-176, 2009 ciently producing an orexin neuron from a pluripotent stem [non-patent document 2] Cell 98: 365-376, 1999 cell or a neural progenitor cell. In addition, the present inven [non-patent document 3] Cell 98: 437-451, 1999 tion relates to a therapeutic agent of narcolepsy or an eating [non-patent document 4] Neuroscience 178: 82-88, 2011 disorder, and to the ?eld of treatment of diseases improved by SUMMARY OF THE INVENTION orexin neuron regeneration. [0003] Orexin is an intracerebral peptide which promotes Problems to be Solved by the Invention wakefulness, and constitutes an orexin regulatory system and plays the central function of regulating wakefulness-sleep via [0008] Destabilization of wakefulness-sleep causes a seri an orexin receptor which is widely distributed in the brain ous brain dysfunction such as reduction in cognitive or learn (Non-Patent Document 1). Experimentally, lack of orexin ing capacity, and leads to deterioration in the brain function. leads to narcolepsy (a pathological condition in which a per Previously, induction of sleep has been tried by a sleep son suddenly and paroxysmally falls into short sleep) (Non inducing drug aiming at improvement in sleep. The orexin Patent Documents 2 and 3). Further, the concentration of action promoter or inhibitor is an extension thereof. However, orexin in the cerebrospinal ?uid of a narcolepsy patient is as particularly, the problem of wakefulness-sleep accompanied low as about 1/3 of that of a healthy person, and decrease in the with aging is a problem of reduction in the quality of sleep or number of orexin neurons is also observed. It has been destabilization of wakefulness-sleep rather than decrease in revealed that the hypofunction of the orexin system in?u the sleeping time. The orexin system is essential for stabili ences on the wakefulness-sleep cycle, and also adversely zation of wakefulness-sleep. When it becomes possible to in?uences on maintenance of homeostasis. The proper activ induce an orexin neuron, this provides a new treatment ity of the orexin system is essential for maintaining normal method covering diseases exhibiting abnormality of the wakefulness-sleep and maintaining homeostasis (N on-Patent wakefulness-sleep cycle. An object of the present invention is Document 4). For this reason, development of an orexin to provide a means for inducing an orexin neuron in vitro. action promoter (agonist) or inhibitor (antagonist) has been [0009] It is said that 0.2% of the world’s population suffers attracting attention. On the other hand, when an orexin pro from narcolepsy. Experimentally, absence of orexin gene or a ducing cell (orexin neuron) is absent or decreased, effective receptor gene thereof causes narcolepsy symptoms; however, ness of such agonists or antagonists is limited. However, until mutation or absence of orexin gene or a receptor gene thereof now, there is no report on successful methods to induce an is rarely seen in the patients. There is no basic therapy for orexin neuron in vivo or in vitro. narcolepsy, and treatment is performed with psychic ener [0004] N-acetyl-D-mannosamine, an isomer of N-acetyl gizer (methylphenidate (Ritalin), Pemoline (Betanamin), D-glucosamine, is known as, for example, a starting material Moda?nil (Modiodal) etc.), as well as psychotropic drugs and for the enzymatic synthesis of sialic acid (N -acetyl anesthetics. However, they are associated with the problem of neuraminic acid), which serves as a medicament and a start drug dependency. The etiology of narcolepsy is a decrease or ing material for other medicaments. Also, N-acetyl-D-man lack of orexin-producing cells. Therefore, the development of nosamine permits enzymatic synthesis of sialic acid a basic therapeutic drug for narcolepsy is desired, and an derivatives from derivatives thereof, hence an industrially object of the present invention is to provide a basic therapeu important substance. In a known method of producing tic drug for narcolepsy. N-acetyl-D-mannosamine, the molar conversion yield of N-acetyl-mannosamine from N-acetyl-glucosamine in Means of Solving the Problems isomerizing the latter under alkaline conditions is increased [0010] The present inventors extensively investigated to by the addition of boric acid or borate (patent reference 1). solve the above-described problems and, as a result, found out Another known method is such that sialic acid, as the sub that by adding N-acetyl-D-mannosamine, or a combination strate, is reacted with N-acetyl-neuraminate lyase to produce of N-acetyl-D-mannosamine with a particular inhibitor to a N-acetyl-D-manno samine (patent reference 2).
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