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(12) Patent Application Publication (10) Pub. No.: US 2016/0243197 A1 G00 Sens (43) Pub

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US 20160243 197A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0243197 A1 G00 sens (43) Pub. Date: Aug. 25, 2016 (54) USE OF GHRELIN ORFUNCTIONAL Publication Classification GHRELIN RECEPTORAGONSTS TO PREVENT AND TREAT STRESS-SENSITIVE (51) Int. Cl. PSYCHATRC LLNESS A638/22 (2006.01) GOIN33/74 (2006.01) (71) Applicant: Massachusetts Institute of Technology, A613 L/435 (2006.01) Cambridge, MA (US) (52) U.S. Cl. CPC ............... A61K 38/22 (2013.01); A61 K3I/435 (72) Inventor: Ki Ann Goosens, Cambridge, MA (US) (2013.01); G0IN33/74 (2013.01); G0IN (73) Assignee: Massachusetts Institute of Technology, 2800/7004 (2013.01); G0IN 2800/54 (2013.01); Cambridge, MA (US) G0IN 2333/575 (2013.01) (21) Appl. No.: 15/052,110 (57) ABSTRACT (22) Filed: Feb. 24, 2016 The invention relates to methods of treating stress-sensitive psychiatric diseases arising from trauma in a Subject by Related U.S. Application Data enhancing ghrelin signaling in the BLA of the Subject. The (60) Provisional application No. 62/119,898, filed on Feb. invention also relates to methods of reversing ghrelin resis 24, 2015. tance. Patent Application Publication Aug. 25, 2016 Sheet 1 of 18 US 2016/0243.197 A1 itediate Baseline Sarapie Auditory fear critioning Sarpie at 8, it, 36, 60, i28, atti i8 it long-term context long-terra Aisitory ear Recai Fair Recai F.G. 1A Patent Application Publication Aug. 25, 2016 Sheet 2 of 18 US 2016/0243.197 A1 10. a 30 s t 60 5 40 s { 200 t 3. 2 8 Minutes. After Fear Conditioning x & 8 2. 5,1600 1200 \ 8 88: 5 400 war - X 3 is 2: 88 inites. After Fear Conditioning F.G. 1B Patent Application Publication Aug. 25, 2016 Sheet 3 of 18 US 2016/0243.197 A1 -k:x:*x -> 8. ai. 2. 283 33 88: S38 88: Agy-Greif 8wes (pgm) & at 29 rain post-concitier8 F.G. 1C Freezing During Auditory Fear Recall w-r- i.ow Ghrein (20-80 mi; average) -&- High (shreiin 20-80 in average & 8. it N iss 40 i. 2 3 4 S f 8 re F.G. 10 Patent Application Publication Aug. 25, 2016 Sheet 4 of 18 US 2016/0243.197 A1 Risk Assessert Eehavior During Auditory Fear Recals 522.7 pg/m. 1 384.2 pg/mL. Acyl-Chrelieves 8 -8-221.5 pginal •:- 248.6 pginal 8 : 384.2 pgin 221.5 pg/ml. c.3: .. 455.7 pgin 3. -x-522.7 pginal 248.6 pg/ml. -x- 63.2 pginal F.G. 1E 8asite ai: 8te: Attitory Feiss Gorditioning long-tefan Context tong-term Auditory saf Reca Seaseca B. S. 2S 38 SS B 8 88 Baseline Acyl-Ghreiin level giml) FG. 2B Patent Application Publication US 2016/0243.197 A1 Patent Application Publication US 2016/0243.197 A1 ####0.3,&######## Patent Application Publication Aug. 25, 2016 Sheet 7 of 18 US 2016/0243.197 A1 i O f to it a is . 5 is ) st or (c. 9 (; c. c. to t e type . pp gap op. c. giga. Apoc 9, Ste) patistics Acotia . s ass s c se (8 as t e c. t;88s. ipos : se patistica Axia Patent Application Publication Aug. 25, 2016 Sheet 8 of 18 US 2016/0243.197 A1 3. s 2 3. WE intra-BLA infusion FG. 3D 14 dimmobilization stress (STR) s weeks ar TailBaseline Bleeding Sacrifice 14 dhianding (NS FG. 4A Patent Application Publication Aug. 25, 2016 Sheet 9 of 18 US 2016/0243197 A1 FG. 4B Patent Application Publication Aug. 25, 2016 Sheet 10 of 18 US 2016/0243.197 A1 388 - x 388 i 8 - i. 8& st &888 s x: 3 * 3888 S. 6888. s 8 : s33 8. S FG. 4C 2 va hy as S a W 1888 o NS R2s 3.893 i SR R2 = 0,847 &W ear-reer were rewa 8M sm - Wea S 1 B 53 253 3: 353 Baseline Acyliehrelin (pgirl FG. 4D Patent Application Publication US 2016/0243.197 A1 y sizea. Patent Application Publication Aug. 25, 2016 Sheet 12 of 18 US 2016/0243.197 A1 Long-term Auditory Fear Recai 8 R = 0.942 p < 0.01 8 s s 3S s SS Acyl-Ghreiin levels (pgiml) 120 min post-conditioning F.G. 5A Long-term Auditory Fear Recall 8 R = 0.926 tra p < 0.01 i t 2s 3S s SS 8s Acyl-Ghrelin Levels (pg/ml) 180 min post-conditioning F.G. 5B Patent Application Publication Aug. 25, 2016 Sheet 13 of 18 US 2016/0243.197 A1 Fear Conditioning -&-ass 8tein (23-338 ::in asseyage s -8-igh &heir 28,333 nir average F.G. SC 1 Long-term Context Fear Recai R* = 0.263 80 p is 0.30 SS o,60 3. as: SS SS Acyl-Ghrein levels (pg|ml) 120-180 min post-conditioning FIG. 5D Patent Application Publication Aug. 25, 2016 Sheet 14 of 18 US 2016/0243.197 A1 28 1 8:3 38 38 (8. 58 38 Acyl-Ghrein levels (pgini) 120-180 min post-conditioning F.G. 5E s *s 8 E is -- irrediately after fear conditioning s -- Without fear conditioning s "es e c . 2, 3 Time (hr) F.G. SF Patent Application Publication Aug. 25, 2016 Sheet 15 of 18 US 2016/0243.197 A1 458 pXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX Acyl-Ghrein 400 358 300 268 ; 280 150 100 so F.G. 5A 383 Corticosterone 983 338 38 888 388 S; 23. lastixia FG. 6B Patent Application Publication Aug. 25, 2016 Sheet 16 of 18 US 2016/0243.197 A1 ce c k { s N to itsaa3. Patent Application Publication Aug. 25, 2016 Sheet 17 of 18 US 2016/0243.197 A1 N g s s ar s : w s tiew poq & se tiedittinside Asciiti s & w t c tifies poca, se trodutinistica not Patent Application Publication Aug. 25, 2016 Sheet 18 of 18 US 2016/0243.197 A1 F.G. 8 3.4.3. 888 8 : 8. 8. 3.8 Attygiaia iucietis FG. 9 US 2016/0243 197 A1 Aug. 25, 2016 USE OF GHRELIN ORFUNCTIONAL cally effective amount of ghrelin or an agent that enhances GHRELIN RECEPTORAGONSTS TO ghrelin signaling in the basolateral complex of the amygdala PREVENT AND TREAT STRESS-SENSITIVE (BLA), within a memory consolidation period following the PSYCHATRC LLNESS trauma exposure. 0005. In some embodiments, the memory consolidation RELATED APPLICATIONS period is 0 hours-1 week, 0 hours-5 days, 0 hours-48 hours, or 0001. This application claims priority under 35 U.S.C. 0-24 hours following the trauma exposure. In some embodi S119(e) to U.S. Provisional Application Ser. No. 62/119,898, ments the memory consolidation period is 0-6 hours follow entitled “USE OF GHRELIN OR FUNCTIONAL GHRE ing the trauma exposure. In some embodiments the memory LIN RECEPTORAGONISTS TO PREVENT AND TREAT consolidation period is 0-1 hour following the trauma expo STRESS-SENSITIVE PSYCHIATRIC ILLNESS filed On SUC. Feb. 24, 2015, which is herein incorporated by reference in its 0006. In some embodiments, ghrelin is administered to the entirety. Subject. In some embodiments, the ghrelin is in the form of acyl-ghrelin. In some embodiments, the agent targets the FEDERALLY SPONSORED RESEARCH ghrelin receptor (GHSR). In some embodiments, the agent is a functional GHSR agonist. For example, the functional 0002 This invention was made with government support GHSRagonist may be: Adenosine, alexamorelin, Anamore under Grant No. W911 NF-10-1-0059 awarded by the U.S. lin, Capromorelin, CP-464709, Cortistatin-14, Examorelin Army Research Office and government support under Grant (hexarelin), Growth Hormone Releasing Peptide-1 (GHRP No. RO1 MH084966 awarded by the National Institutes of 1), Growth Hormone Releasing Peptide-2 (GHRP-2), Health. The government has certain rights in the invention. Growth Hormone Releasing Peptide-3 (GHRP-3), Growth Hormone Releasing Peptide-4 (GHRP-4), Growth Hormone BACKGROUND OF INVENTION Releasing Peptide-5 (GHRP-5), Growth Hormone Releasing 0003 Ghrelin, often called “the hunger hormone', is an Peptide-6 (GHRP-6), Hexamorelin, Ibutamoren (MK-677), omnipresent circulating hormone that is released by the stom Ibutamoren mesylate (IBU), Ipamorelin, L-692585, ach and other peripheral organs into the bloodstream. In its LY-426410, LY-444711, Macimorelin, Pralmorelin, Relamo acylated form (acyl-ghrelin), it can cross the blood-brain relin, SM-130,686, Tabimorelin, Ulimorelin, or combination barrier and bind to central ghrelin receptors (growth hormone thereof. In some embodiments, the functional ghrelin recep secretagogue receptor 1a, or GHSR). GHSRs are abundant in toragonist is ibutamoren mesylate (IBU). classic hypothalamic hunger regions. Also, ghrelin levels can 0007. In some embodiments, the agent is a compound that be rapidly elevated within minutes during anticipatory hunger enhances or facilitates the synthesis or release of ghrelin from states. GHSRs are widely distributed throughout the brain the stomach. including brain regions not typically associated with hunger, 0008. In some embodiments, the agent is a compound that Such as the basolateral complex of the amygdala (BLA), a enhances or facilitates the acylation of ghrelin. brain region important for regulating fear. There are many 0009. In some embodiments, the agent is a compound that contradictory findings on the role of the hormone ghrelin in reduces or decreases the de-acylation or breakdown of ghre aversive processing. lin. 0010. In some embodiments, a therapeutically effective SUMMARY OF INVENTION amount of ghrelin and the agent that enhances ghrelin signal 0004. The present disclosure provides several surprising ing is administered. findings. For instance, in unstressed subjects, endogenous 0011. In some embodiments, wherein the administering is peripheral acyl-ghrelin robustly inhibits fear memory con via systemic administration, injection, or infusion directly Solidation through actions in the amygdala.
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    Aus der Urologischen Klinik und Poliklinik der Ludwig-Maximilians-Universität München Direktor: Prof. Dr. Christian G. Stief Effect of ghrelin receptor ligands on proliferation of prostate stromal cells and on smooth muscle contraction in the human prostate Dissertation zum Erwerb des Doktorgrades der Medizin an der Medizinischen Fakultät der Ludwig-Maximilians-Universität zu München vorgelegt von Xiaolong Wang aus Wuhan, China 2020 Mit Genehmigung der Medizinischen Fakultät der Universität München Berichterstatter: Prof. Dr. rer. nat. Martin Hennenberg Mitberichterstatter: PD Dr. Heike Pohla Prof. Dr. Wolf Mutschler Dekan: Prof. Dr. med. dent. Reinhard Hickel Tag der mündlichen Prüfung: 20.02.2020 1. Introduction ........................................................................................ 1 1.1 Definition of LUTS .......................................................................... 1 1.2 Epidemiology, etiology and nature history of LUTS ................... 2 1.3 Pathogenesis of LUTS suggestive to BPH ..................................... 4 1.3.1 Age .............................................................................................. 6 1.3.2 Inflammation ............................................................................... 6 1.3.3 Sex hormones .............................................................................. 7 1.3.4. Metabolic factors ....................................................................... 7 1.3.5 Other urologic diseases associated with LUTS .......................... 9