THELA TARDE DINEUS 20180085423A1 HII NAKUWA NA MATATU ( 19) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2018 / 0085423 A1 ZELTSER et al. (43 ) Pub . Date : Mar . 29 , 2018 ( 54 ) METHODS FOR TREATING AND ( 60 ) Provisional application No . 62 / 148, 698 , filed on Apr . DIAGNOSING EATING DISORDERS 16 , 2015 . ( 71 ) Applicant: THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF Publication Classification NEW YORK , New York , NY (US ) (51 ) Int. Cl. A61K 38 / 08 ( 2006 .01 ) ( 72 ) Inventors : Lori Michelle ZELTSER , New York , A61K 9 / 00 (2006 . 01) NY (US ) ; Rim HASSOUNA , New (52 ) U . S . CI. York , NY (US ) ; Moneek MADRA , CPC . .. .. A61K 38 /08 (2013 .01 ) ; A61K 9 /0019 New York , NY (US ) ( 2013 .01 ) (73 ) Assignee : THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF ( 57 ) ABSTRACT NEW YORK , New York , NY ( US) The present invention provides methods of treating or pre venting an eating disorder , including anorexia nervosa, by ( 21 ) Appl. No. : 15 / 784, 927 administering a vasopressin Vla receptor (AVPR1A ) antago (22 ) Filed : Oct. 16 , 2017 nist. The present invention also provides methods of diag nosing the presence of or predisposition to an eating disor Related U . S . Application Data der, including anorexia nervosa, in a subject , comprising (63 ) Continuation - in -part of application No . PCT /US16 / detecting the presence and / or level of arginine vasopressin 25209, filed on Mar . 31, 2016 . ( AVP ) or AVPR1A in a the subject. Patent Application Publication Mar .29 , 2018 Sheet l of 15 US 2018 / 0085423 A1 FIGERES LA . C ? , ? . inBeiMiki ?????: ?????????????????????????? … … … * * * * * * * * *. *. A. A4. A. 4. A. 4. A . is: www … … … . ? , ? ? : : : : : * … . * adidas …. … * .… 32? Patent Application Publication Mar . 29 , 2018 Sheet 2 of 15 US 2018 / 0085423 A1 FIGURES 2A - E * .. * volano33120)( Aclaruma * Against * & renk GES e cop Genadype Vai Very VaVa fer ? Valla Vet ? Ket ? Me ? Socialisolation Swks Swks 52V4S SES Swks Swks Caloxio restrictions : ?Wawks 9002 7wks we erale siis 60 Vaivat, isolated CR 660 Meti ? , solated , CR * 8 * . RUGOMBEIGUOA( VORM wwwwwwwww Time ( days) Gengiyon Vaiwa Beyin Socialisation ms Ssuks . Caloric restriction 70ks !uks Patent Application Publication Mar . 29 , 2018 Sheet 3 of 15 US 2018 / 0085423 A1 FIGURES 3A - D FIGURE 3A FIGURE 3B GE : Marcolets QED : Met ? Soate . CR . ' BELRIES Animal -. * 0 @ Gento . Ma Me Wet ' ? We Sock soku wkS is ots Swis Czerc tastietoa 7KS KS Age of addiya : 7 . 9 XKS 9 Suks 7 . 9 .5wks vs FIGURE 3C Aegningai ?????????? GE GED GER GEDI Genovo M Mer Mers Focal 5W * S XS SWS Cok * * 9Sokie stort . - W WYS Zwks Caic restriction levels FIGURE 3D everything Pu ;???????????.????????????????????????????????????????????????????????? www GEO GEO GERD EO seg Caloge . Motor ? VoW VO VW Soosao Swisks SWS SKS AWS CHem WSW wts was awks Basi - Patent Application Publication Mar . 29 , 2018 Sheet 4 of 15 US 2018 / 0085423 A1 FIGURES 4A - C FIGURE 4A Es coin DocemucoucoWines Ouru) wwwwwwwwwwwwwwwww GED-6 CEDAE GEDH FIGURE 4B x in RelativeRIAvoriaugge-uossadxo dewiii GEDOGEDAE GEDH FIGURE 4C o ? ina RelativePTAvonta Expression(B-scani ? o ? GEDGED -AE CED Patent Application Publication Mar . 29 , 2018 Sheet 5 of 15 US 2018 / 0085423 A1 FIGURES 5A - C FIGURE 5A ??.???????????????????????????????????? vogelduOUOOWNBS (wow! 0 G GE FIGURE 5B (unde-il)voiss?loxe LOAFUdang 1 C . GE GE FIGURE 5C expression(ft-actin . FelativePITaprId nes. C G EGE Patent Application Publication Mar . 29 , 2018 Sheet 6 of 15 US 2018 / 0085423 A1 FIGURES 6A - E FIGURE 6A FIGURE 6B * ANG : AVO AMG : Avoria B . Relativeexpression f-actin torstadoSAMO (B-actio) C G D GE G dengan GE FIGURE 6C FIGURE 6D . PFO : Avoria AC: Avoria 2-22222222 BAJOdx9voissa. (une-) 04. Relativeexpression 6-act © GECE FIGURE 6E 0dH qurday MOSSJoxeonneay (-actin) 2 C G GE Patent Application Publication Mar . 29 , 2018 Sheet 7 of 15 US 2018 / 0085423 A1 FIGURES 7A - G FIGURE A FIGURE 7B 200 .000 190. 000 T L counts) * Totalactivity(counts) KISWA MILARDEPORNO 99 .000 Genotype Verval meu ? Vama Ves ? Valva Very Vama Seu ? Skaistian - WS - 1 SWS SWS Movel environmentEuli: 6 - 765 6 -7XS 6 - wks 6 -7wks lili FIGURE 7C FIGURE 7D FIGURE 7E R HYP -Ohr R HYP : 0 to RHYO :Crir > * > e *. (P-actist) (B-actin) iet m (6-sotin Relativeexpression toissaldosajejo Relativeexpression .* N wwwwwwwwwwwwww o C G G C 6 GE FIGURE 7F FIGURE 7G Saseline 0 Absolute dhcrease mare wwwww (ng/dL)file (ng/dL) celemai QuojasOODOO B 4444444 Corticosterone @ GED - 0 GED -AS GED . GED -AE Patent Application Publication Mar . 29 , 2018 Sheet 8 of 15 US 2018 / 0085423 A1 FIGURES 8A - F FIGURE 8A FIGURE SB . o WdAH ild Owuod *ngingin Relativeexpression (B-acun topo Relativeexpression(unge-91) seminarioesconditioniniocom* C G GE CGGE FIGURE THI8C FIGURE 8D Adrenalweight baseline restraint * UQSisomopów)( (bbw)14610M 890 * jeuaipeajela WWWWWWWWWW ? 88 * GGE. C. G GE Patent Application Publication Mar . 29 , 2018 Sheet 9 of 15 US 2018 / 0085423 A1 FIGURE SE (counts) Centraltotalactivity ???????.??????????????????????????????????? C GEGE Genotype : Valdal Met ? Val/ Val Met ? Social isolation : 5 -6wks 5 -6wks Novel environment: 6 -7wks 6 - 7wks 6 - 7wks 6 - 7wks FIGURE 8F 200000. - Totalactivity(counts) 50000 C G E GE Patent Application Publication Mar . 29 , 2018 Sheet 10 of 15 US 2018 /0085423 A1 FIGURES 9A - B FIGURE 9A AE/animal W wwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwww ww GE GEDH Genotype Met ? Met ? Social isolation : 5wks 5wks Caloric restriction : 7wks 7wks Handling 2 6wks FIGURE 9B R88 WLLLL LLLLLLLLLL Corticosterone(ug/dL) * * * www.qwqwyu? * 89 ??????????????????????????? * ??? GEDH baseline O restraint Patent Application Publication Mar . 29 , 2018 Sheet 11 of 15 US 2018 /0085423 A1 FIGURES 10A - D FIGURE 10A FIGURE 10B FIGURE 10C FIGURE 10D * * .. * X * BOX * ,.4 X*XXKM W ,. , , * * mmmmmmm 6 : * Serum AVP AMYG"! :Avprla "! "! AMYG :Avp AMYG: Ngfr Patent Application Publicati0ll Mar . 29 , 2018 Sheet 12 0f15 US 2018/ 0085423 Al FIGURE11 Saline GED - AE Corripound 1 ug/ kg GED - AE A Saline WT- Fasted ? f Commpound 1 ug / kg NT -Fasted 1? CurmulativefoodIntake(g) ? ? ?3 G84 ?-1. | _.i• 1:4 ? ? ?? ? ? His ? 2h Time after injection Patent Application Publication Mar . 29 , 2018 Sheet 13 of 15 US 2018 /0085423 A1 FIGURES 12A - I 0062656 :40 12: 45 065 : 8 ) VAGINAS GENERIC MOMENTAS YEAR 30 MM S . ad rem o con GSA3254 wie ( 66 .6802 uselesa: 0004 o 12 mescissis 6 628105 We 8x8 Axence . Sms Sport kuoad Mediat Sook c xana Avota Aloto highesiaktive i 2000 . : . 2403Skogi?i Quoo 1. las Rediveakiyesion tn:act PEG LOIESAISXSStuckyCongo XXIKVRUSAK os 20003 - C AME s90 CEDO GEDAAN ROM root BONE Vacant Our valle 60X100 Sot RÓKI Socis solajor Sms Sc404 S04 13 . 8 .. BIORESO Cabric tesko * . Cantoresco algoYesuais wska Dvorts Airo M ees voor 1000043 Backin) (092-300 acra asoch8/10800 NOSRXONAawe enon plavespesso Piana4veroom on goa * G SE 96 *!W SON 768xe ! . CONV:58 0.4 DONE sfonat o rer : * LLLSocial Scinoo . * Soch saken soosis : 0 j Socet Isocom : Patent Application Publication Mar . 29 , 2018 Sheet 14 of 15 US 2018 /0085423 A1 FIGURES 13A - C . :'d D Saline Wild type AVP 0. 03ng 16 per group Cumulativefoodintake(9) 30 min 1 2h 4h Tints after injection 0 Saline AVP 0 .0300 AVPR1A KO n - 4 per zroup cumulaivefoodintake(0) 30 mini 11 21 h ?????? {{ ?? ? Patent Application Publication Mar . 29 , 2018 Sheet 15 of 15 US 2018 /0085423 A1 FIGURES 14A - B B 63line 103. Saline 1. .. AVPCV Saline ja m AvoicV Manning Compounds. * AVPLOV * R49050 1. D . Ourrulauvafoodintake(9) . ac bo W Time after injection O Salne CED - AE m Manning Compound GEO -AE W SR49059 GEO -AE g Sahne W - Fastad . Curnulativefoodintake( . 24 Time after injection (saline , avp + saline , avp +manning , avp + SR49059 ;75 , 4 , 5 , 4 ) (GED -AE saline , Manning , SR49059 ; n = 4 , 4 , 3 ) (WT saline, Manning SR49059 , n = 10 . 5 , 5 ) US 2018 /0085423 A1 Mar . 29 , 2018 METHODS FOR TREATING AND receptor antagonist to the subject, to thereby modulate DIAGNOSING EATING DISORDERS eating behavior in the subject . [0007 ] In one embodiment of the foregoing aspects, the RELATED APPLICATIONS vasopressin V , receptor antagonist can be , for example , a small molecule antagonist, such as, but not limited to , [0001 ] This application is a continuation -in -part of Inter 1 - (beta -mercapto -beta beta - cyclopentamethylenepropionic national Application No. PCT/ US2016 /025209 , filed Mar. acid ) - 2 - ( 0 -methyl - Tyr ) -argipressin , SR49049 (Relcovap 31 , 2016 , which claims the benefit of priority to U . S . tan ) , atosiban ( Tractocile® ) , conivaptan ( YM - 087 ) , VPA Provisional Patent Application No. 62 / 148 ,698 , filed Apr. 985 (Lixivaptan ), CL - 385004 , Vasotocin , SRX251 and 16 , 2015 . The contents of these applications are incorporated SRX246 ( Azevan ) , YM - 218 (Astellas ), OPC -2158 ( Otsuka ), herein by reference in their entirety . and OPC21268 , or a pharmaceutically acceptable salt thereof. SEQUENCE LISTING [ 0008 ] In another embodiment of the foregoing aspects , [0002 ] The instant application contains a Sequence Listing the vasopressin Vla receptor antagonist is selected from the which has been submitted electronically in ASCII format group consisting of a small interfering RNA (siRNA ), a and is hereby incorporated by reference in its entirety . Said microRNA , an antisense nucleic acid , a ribozyme, an anti ASCII copy , created on Oct . 16 , 2017 , is named 123756 body , and a peptide or peptide analogue . 00202 _ SL . txt and is 18 ,622 bytes in size . [ 0009 ] In another embodiment of the foregoing aspects , wherein the vasopressin Vla receptor antagonist does not BACKGROUND cross the blood brain barrier. In another embodiment of the foregoing aspects , the vasopressin Vla receptor antagonist [ 0003 ] Anorexia nervosa is an eating disorder character does cross the blood brain barrier . In another embodiment of ized by food restriction , odd eating habits or rituals , obses the foregoing aspects , the Vla receptor antagonist is admin sion with having a thin figure , and an irrational fear of istered via injection . In another embodiment of the forego weight gain .