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(12) United States Patent (10) Patent No.: US 8,604,011 B2 Melon (45) Date of Patent: Dec

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(12) United States Patent (10) Patent No.: US 8,604,011 B2 Melon (45) Date of Patent: Dec USOO8604011 B2 (12) United States Patent (10) Patent No.: US 8,604,011 B2 MelOn (45) Date of Patent: Dec. 10, 2013 (54) THERAPY FORTREATMENT OF CHRONIC OTHER PUBLICATIONS DEGENERATIVE BRAIN DISEASES AND NERVOUS SYSTEM INJURY Frolov (The JBC, 2003, 278, 28, p. 25517-25525).* NINDS, NIH document (http://www.ninds.nih.gov/disorders/ (75) Inventor: Synthia Mellon, San Francisco, CA niemann/niemann.htm), 2010, p. 1-2.* (US) Timby, Gynecological Endocrinology, 2010, p. 1-7.* Mellon (Brain Research Reviews, 2008, 410-420).* 73) Assignee:9. The Regentsg of the UniversitVy of Burns et al. (Nature Medicine, vol. 10, 7, Jul. 2004).* California, Oakland, CA (US) Bramlett, K. S. et al., “A Natural Product Ligand of the Oxysterol Receptor, Liver X Receptor'. The Journal of Pharmacology and *) Notice: Subject to anyy disclaimer, the term of this Experimental Therapeutics, vol. 307, pp. 291-296 (2003). patent is extended or adjusted under 35 Collins, Jon L., “Therapeutic opportunities for liver X receptor U.S.C. 154(b) by 781 days. modulators'. Current Opinion in Drug Discovery & Development, vol. 7, No. 5, pp. 692-702 (2004). Griffin, Lisa D. et al., “Niemann-Pick type C disease involves dis (21) Appl. No.: 11/576,125 rupted neurosteroidogenesis and responds to allopregnanolone'. (22) PCT Filed: Sep. 27, 2005 Nature Medicine, vol. 10, No. 7, pp. 704-711 (2004). di Michelle, F. et al., “Decreased plasma and cerebrospinal fluid (86). PCT No.: PCT/US2OOS/O34746 content of neuroactive steroids in Parkinson's disease'. Neurol. Sci. vol. 24, pp. 172-173 (2003). S371 (c)(1), Reddy, D. S., “Pharmacology of Endogenous Neuroactive Steroids'. (2), (4) Date: May 13, 2008 Critical Reviews in Nerobiology, vol. 15, No. 3&4, pp. 197-234 (2003). (87) PCT Pub. No.: WO2006/037016 Rupprecht, R., “Neuroactive steroids: mechanisms of action and neuropsychopharmacological properties'. Psychoneuroendocrinol PCT Pub. Date: Apr. 6, 2006 ogy, vol. 28, pp. 139-168 (2003). Weill-Engerer, S. et al., “Neurosteroid Quantification in Human (65) Prior Publication Data Brain Regions: Comparison between Alzheimer's and Nondemented US 2008/0269.183 A1 Oct. 30, 2008 Patients'. The Journal of Clinical Endocrinology, vol. 87, No. 11, pp. 5138-5143 (2002). Related U.S. Application Data * cited by examiner (60) Provisional application No. 60/613,880, filed on Sep. 27, 2004. Primary Examiner — Sreeni Padmanabhan (51) Int. Cl. Assistant Examiner — Uma Ramachandran A6 IK3I/56 (2006.01) (74) Attorney, Agent, or Firm — Morgan, Lewis & Bockius A 6LX3/57 (2006.01) LLP: Jeffry S. Mann A6IP 25/00 (2006.01) A6IP 25/28 (2006.01) (52) U.S. Cl. (57) ABSTRACT USPC ........................................... 514/177, 514/182 (58) Field of Classification Search In one aspect the present invention provides neuroactive Ste USPC .................................................. 514/182, 177 roids for use in the treatment of nervous system disorders, See application file for complete search history. degenerative brain diseases and congenital storage diseases. In a second aspect the invention provides neuroactive steroids (56) References Cited in combination with a Liver X Receptor (LXR) ligand to effect treatment of a nervous system condition. U.S. PATENT DOCUMENTS 2005.0003998 A1 1/2005 Bertilsson et al. ................ 514f1 7 Claims, 8 Drawing Sheets U.S. Patent Dec. 10, 2013 Sheet 1 of 8 US 8,604,011 B2 Figure 1 A. B. NP-C ALLO P7 1000 NP-9 sis; srs GM3 1S 800 Al-Q P10 GM2 3 ALLO P7 GM1 gig32 600 (5 9E 400 2 O O GM3 GM2 GM1 U.S. Patent Dec. 10, 2013 Sheet 2 of 8 US 8,604,011 B2 Figure 2 CEREBELLUM NP-C k2 taxa: U.S. Patent Dec. 10, 2013 Sheet 3 of 8 US 8,604,011 B2 Figure 3 THALAMUS/HYPOTHALAMUS GM1 U.S. Patent Dec. 10, 2013 Sheet 4 of 8 US 8,604,011 B2 Figure 4 MACTHALAMUS NPC ALLOP7 WLD TYPE MHC HALANUS NP-C ALOP7 WILDTYPE U.S. Patent Dec. 10, 2013 Sheet 5 of 8 US 8,604,011 B2 Figure 5 P & O.001 Wild type 4 O O P7-treated NP-C untreated TNF TGF1 Lif Cytokine U.S. Patent Dec. 10, 2013 Sheet 6 of 8 US 8,604,011 B2 Figure 6 Stimulation of NGF Secretion Effect of ALLO O neurotrophin secretion from cerebellar astrocytes. Pure cultures of cerebellar astrocytes from P3 cerebella were Cultured 92 24 hours for 1-3 days it 10 nM ALLO, and e a 48 hours NGF was assayed every 24 hr d 72 hours by ELISA. t c 2. 4.6OO OO Control ALLO (10 nM) Astocytes Astrocytes U.S. Patent Dec. 10, 2013 Sheet 7 of 8 US 8,604,011 B2 Figure 7 Survival Ganaxolone: weight 10 soro Untreated are Ganaxoo. P. 60 ason Untreated O O 25 50 is 100 12s 150 O 8 2 6 2. Age days) Age (weeks) Onset of symptoms O Terror nset of symptoms as Ataxi Untreated occa Weight loss PC: 0.001 too case Ganxolone P7 P & O,02 g s s s S 2s 23 o lateated eats close Atala Weight loss Teatre Symptom Ganaxolone: coordination Ganaxolone: locomotion 2 o E 10 sa 16 8 9. 9. 12 4. -- Untreated 8 8 Untreated 8 word-Ganator Pt -- Ganaxolone P7 -v- W aer W 8 12 14, 16 18 2 0 2 4 6 8 to 12 14 16 18 20 Age (weeks) Age (weeks) U.S. Patent Dec. 10, 2013 Sheet 8 of 8 US 8,604,011 B2 Figure 8 600 SOO -- Untreated g 400 or or LXR e 300 widor ALLO -- LXRIALLO s 200 100 ne 28 42 56 70 84 98 12 126 40 Age (days) 100-E-R-E-HHHE-R-E-R-E-F-R-F 80 -B- Untreated 60 -- LXR -H ALLO 40 -- LXRWALLO R 20 O O 14, 28 42 56 7O 84 98 12 126 140 Age (days) US 8,604,011 B2 1. 2 THERAPY FORTREATMENT OF CHRONIC ease is manifest. Thus, Strategies for the treatment of these DEGENERATIVE BRAIN DISEASES AND debilitating and often fatal diseases often focus primarily on NERVOUS SYSTEM INJURY pallative measures. Attempts at curing neurological disease have also been proposed. These treatments have included RELATED APPLICATIONS enzyme replacement therapy, gene therapy, and allogenic bone marrow transplantation. Unfortunately however, the This application claims priority to U.S. Provisional Patent treatments typically do not improve the condition nor alter the Application No. 60/613,880, filed Sep. 27, 2004, which is ultimate outcome of the disease. Thus, before this invention, herein incorporated by reference in its entirety. symptomatic management was often the only approach avail 10 able for treating most of these disorders. STATEMENT AS TO RIGHTS TO INVENTIONS The present inventors have determined for the first time MADE UNDER FEDERALLY SPONSORED that the use of neuroactive steroids is effective for the treat RESEARCH ORDEVELOPMENT ment of degenerative brain diseases and central nervous sys tem disorders. This invention was made with Government support under 15 Managing the neuropathologic processes that contribute to Grant No. HD27970 awarded by the National Institute of the morbidity of neurologic diseases has proven to be a chal Health to Synthia H. Mellon. The Government has certain lenging task, since as noted above, there are many factors that rights in this invention. can cause, perpetuate, or exacerbate neurological conditions involving the central nervous system. There has been no BACKGROUND OF THE INVENTION evidence prior to this invention that neuroactive steroids would provide effective therapy for the treatment of a wide 1. Field of the Invention range of neurological diseases, including congenital lipid The present invention relates to methods of providing storage diseases, inflammatory diseases, and chronic degen therapy for nervous system conditions including, but not lim erative brain disease. The present invention therefore fulfills ited to: degenerative brain diseases, ganglioside storage dis 25 the need for an effective method of treating neurological orders and inflammatory disorders. disorders by providing methods of administering neuroactive 2. Background steriods to a subject. There are more than 600 known disorders that afflict the nervous system. Nervous system disorders have varied eti BRIEF DESCRIPTION OF THE DRAWINGS ologies, but ultimately all have devastating effects on the 30 individuals suffering from them. Nervous system disorders FIG. 1: Ganglioside profiles in cortex from Neimann Pick include degenerative conditions such as Parkinson’s and type-C (NP-C) mice treated with allopregnanolone. (a) High Alzheimer's disease; inflammatory diseases such as Multiple performance TLC profile of gangliosides from untreated Sclerosis, spinal cord injury ischemia and stroke, psychiatric (left) and day 7-treated (right) NP-C mice. (b) Quantitative disorders such as Schizophrenia, and lipid storage disorders 35 data for gangliosides GM2, GM3 and GM1 in the cortex from such as Neimann-Pick-C, Tay Sachs, Batten, Sandhoff and untreated, day 10- and day-7-treated NP-C mice. Individual Gaucher disease. gangliosides are expressed as nanomoles of ganglioside per Neurological disorders strike an estimated 50 million gram of wet weight of tissue (n=3 untreated, n=2 day Americans each year, exacting an incalculable personal toll 10-treated, and n=4 day 7-treated NP-C mice; data are the and an annual economic cost of hundreds of billions of dollars 40 meants.d.; **P<0.001). in medical expenses and lost productivity. FIG. 2: Immunostaining for gangliosides GM1 and GM2, The burden of neurological disease is a burden borne by and for CD4" and for CD8" T cells in adult (60-day old) every segment of Society, and people everywhere. Indeed, mouse brains. Cerebellum. There is virtually no GM1 or GM2 individuals suffering from nervous system disorders often a immunostaining in wildtype mouse cerebella, and only slight require care 24 hours a day, seven days a week.
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