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(12) Patent Application Publication (10) Pub. No.: US 2007/0078083 A1 Barlow Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2007/0078083 A1 Barlow Et Al US 20070078083A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0078083 A1 Barlow et al. (43) Pub. Date: Apr. 5, 2007 (54) MODULATION OF NEUORGENESIS BY Related U.S. Application Data HDAC INHIBITION (60) Provisional application No. 60/715.219, filed on Sep. (75) Inventors: Carrolee Barlow, Del Mar, CA (US); 7, 2005. Provisional application No. 60/764.963, filed Todd A. Carter, San Diego, CA (US); on Feb. 3, 2006. Provisional application No. 60/785, Kym I. Lorrain, San Diego, CA (US); 713, filed on Mar. 24, 2006. Jammieson C. Pires, San Diego, CA (US); Andrew Morse, San Diego, CA Publication Classification (US); Dana Gitnick, San Marcos, CA (US); Kai Treuner, San Diego, CA (51) Int. Cl. (US); Alejandro R. Dearie, Chula A6II 38/12 (2006.01) Vista, CA (US) A6II 3/19 (2006.01) (52) U.S. Cl. ................................................. 514/9: 514/575 Correspondence Address: TOWNSEND AND TOWNSEND AND CREW, LLP (57) ABSTRACT TWO EMBARCADERO CENTER EIGHTH FLOOR The instant disclosure describes methods for treating dis SAN FRANCISCO, CA 94111-3834 (US) eases and conditions of the central and peripheral nervous (73) Assignee: BrainCells, Inc., San Diego, CA (US) system by stimulating or increasing neurogenesis. The dis closure includes compositions and methods based on an (21) Appl. No.: 11/470,957 HDac inhibitory agent alone or in combination with another neurogenic agent to stimulate or activate the formation of (22) Filed: Sep. 7, 2006 new nerve cells. Patent Application Publication Apr. 5, 2007 Sheet 1 of 13 US 2007/0078083 A1 Fig 1 Neuronal Differentiation (TUJ1) 120 Run A 110 O Run B 100 -11.5 - 11.0 -10.5 -10.0 -9.5 -9.0 -8.5 -8.0 -7.5 -7.0 Log Conc (M) Patent Application Publication Apr. 5, 2007 Sheet 2 of 13 US 2007/0078083 A1 Fig 2 Astrocyte Differentiation (GFAP) 140 Run A 130 o Run B to 120 110 o 100 ( ) 90 9 80 E 70 O() 60 al 50 s 40 E 30 CD 20 s 10 O) O -10 -11.5 -11.0 -10.5 -10.0 -9.5 -9.0 -8.5 -8.0 -7.5 -7.0 Log ConC (M) Patent Application Publication Apr. 5, 2007 Sheet 3 of 13 US 2007/0078083 A1 Fig 3 Cell Count 130 120 110 100 90 80 70 60 50 40 30 20 10 11.5 - 11.0 -10.5 - 10.0 -9.5 -9.0 -8.5 -8.0 -7.5 -7.0 Log Conc (M) Patent Application Publication Apr. 5, 2007 Sheet 4 of 13 US 2007/0078083 A1 Fig. 4 250 NFH 200 150 i 100 50 Patent Application Publication Apr. 5, 2007 Sheet 5 of 13 US 2007/0078083 A1 Fig 5 500 GAP43 400 300 200 100 Patent Application Publication Apr. 5, 2007 Sheet 6 of 13 US 2007/0078083 A1 Fig 6 NFH Patent Application Publication Apr. 5, 2007 Sheet 7 of 13 US 2007/0078083 A1 Fig 7 GAP43 Patent Application Publication Apr. 5, 2007 Sheet 8 of 13 US 2007/0078083 A1 Fig 8 NFH Patent Application Publication Apr. 5, 2007 Sheet 9 of 13 US 2007/0078083 A1 Fig 9 100 GAP43 80 60 40 20 Patent Application Publication Apr. 5, 2007 Sheet 10 of 13 US 2007/0078083 A1 Fig 10 7OOO 6000 5OOO 4000 3000 2000 1000 Vehicle Walproic Acid (300mpk) Patent Application Publication Apr. 5, 2007 Sheet 11 of 13 US 2007/0078083 A1 Fig 11 Valproic Acid Human Neurogenesis Assay 110 100 O Astrocyte Differentation Log Conc (M) Patent Application Publication Apr. 5, 2007 Sheet 12 of 13 US 2007/0078083 A1 Fig 12 Valproic Acid Human Toxicity Assay O 100 Control Cell Count Log Conc (M) Patent Application Publication Apr. 5, 2007 Sheet 13 of 13 US 2007/0078083 A1 Fig 13 -0 - Standard Media -HValproic Acid Day 0 Day 7 Day 14 Days of Growth US 2007/0078083 A1 Apr. 5, 2007 MODULATION OF NEUORGENESIS BY HDAC and 7. In vivo, the acetylation state of chromatin is thought INHIBITION to be maintained by a dynamic balance between the activi ties of HATs and HDacs. CROSS-REFERENCES TO RELATED 0005 Some small molecules have been reported as hav APPLICATIONS ing HDac inhibitory activity (HDac inhibitors). HDac 0001. This application claims benefit of priority under 35 inhibitors are thought to shift the HDac/HAT balance U.S.C. S 119(e) from U.S. Provisional Patent Applications towards HAT activity, causing an accumulation of acetylated 60/715.219, filed Sep. 7, 2005; 60/764.963, filed Feb. 3, histones. HDac inhibitors have been reported as associated 2006; 60/785,713, filed Mar. 24, 2006; all three of which are with a diverse range of biological effects, including the hereby incorporated by reference as if fully set forth. induction of cell cycle arrest, terminal differentiation, and apoptosis. HDac inhibitors have also been shown to inhibit FIELD OF THE DISCLOSURE tumor formation in animal models, and a number of com pounds are currently in Phase I and Phase II clinical trials as 0002 The instant disclosure relates to methods for treat potential therapeutics for a variety of cancers. However, to ing diseases and conditions of the central and peripheral date, the role of HDac inhibitors in the central and peripheral nervous system by stimulating or increasing neurogenesis nervous systems has not been fully elucidated. via inhibition of histone deacetylase (HDac) activity, includ ing via inhibition of the activity in combination with another 0006 Citation of the above documents is not intended as neurogenic agent. The disclosure includes methods based on an admission that any of the foregoing is pertinent prior art. the application of a neurogenesis modulating agent having All statements as to the date or representation as to the inhibitory activity against HDac activity to stimulate or contents of these documents is based on the information activate the formation of new nerve cells. available to the applicant and does not constitute any admis sion as to the correctness of the dates or contents of these BACKGROUND OF THE DISCLOSURE documents. 0003) Neurogenesis is a vital process in the brains of BRIEF SUMMARY OF THE DISCLOSURE animals and humans, whereby new nerve cells are continu ously generated throughout the life span of the organism. 0007 Disclosed herein are compositions and methods for The newly born cells are able to differentiate into functional the prophylaxis and treatment of diseases, conditions and cells of the central nervous system and integrate into exist injuries of the central and peripheral nervous systems by ing neural circuits in the brain. Neurogenesis is known to stimulating or increasing neurogenesis. Aspects of the meth persist throughout adulthood in two regions of the mamma ods, and activities of the compositions, include increasing or lian brain: the subventricular Zone (SVZ) of the lateral potentiating neurogenesis in cases of a disease, disorder, or Ventricles and the dentate gyrus of the hippocampus. In these condition of the nervous system. Embodiments of the dis regions, multipotent neural progenitor cells (NPCs) continue closure include methods of treating a neurodegenerative to divide and give rise to new functional neurons and glial disorder, neurological trauma including brain or central cells (for review Gage 2000). It has been shown that a nervous system trauma and/or recovery therefrom, depres variety of factors can stimulate adult hippocampal neuro Sion, anxiety, psychosis, learning and memory disorders, and genesis, e.g., adrenalectomy, Voluntary exercise, enriched ischemia of the central and/or peripheral nervous systems. In environment, hippocampus dependent learning and anti other embodiments, the disclosed methods are used to depressants (Yehuda 1989, van Praag 1999, Brown J 2003, improve cognitive outcomes and treat epilepsy. Gould 1999, Malberg 2000, Santarelli 2003). Other factors, 0008. In one aspect, methods of modulating, such as by Such as adrenal hormones, stress, age and drugs of abuse stimulating or increasing, neurogenesis are disclosed. The negatively influence neurogenesis (Cameron 1994, McEwen neurogenesis may be at the level of a cell or tissue. The cell 1999, Kuhn 1996, Eisch 2004). or tissue may be present in an animal Subject or a human being, or alternatively be in an in vitro or ex vivo setting. In 0004. In eukaryotic cells, nuclear DNA wraps around a Some embodiments, neurogenesis is stimulated or increased protein core consisting of histones H2A, H2B, H3, and H4 in a neural cell or tissue. Such as that of the central or to form chromatin, with basic amino acids of the histones peripheral nervous system of an animal or human being. In interacting with negatively charged phosphate groups of the other embodiments, neurogenesis may be potentiated in a DNA. Approximately 146 base pairs of DNA wrap around neural cell or tissue. In cases of an animal or human, the a histone core to make up a nucleosome particle, the methods may be practiced in connection with one or more repeating structural motif of chromatin. Histones are subject disease, disorder, or condition of the nervous system as to posttranslational acetylation of the C.e-amino groups of present in the animal or human Subject. Thus, embodiments N-terminal lysine residues. The acetylation reaction is cata disclosed herein include methods of treating a disease, lyzed by enzymes termed histone acetyl transferase (HATs). disorder, or condition by administering at least one neuro Acetylation neutralizes the positive charge of the lysine side genesis modulating agent having inhibitory activity against chain, and is thought to impact chromatin structure in a manner that facilitates transcription (e.g., by allowing tran histone deacetylase (HDac) activity. The agent is hereinafter scription factors increased access to DNA). A family of referred to as a “neurogenic HDac inhibitor or a “neuro enzymes termed histone deacetylases (HDacs) has been modulating HDac inhibitor or an “HDac inhibitory agent.” reported to reverse histone acetylation.
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