WO 2007/053596 Al
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(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date (10) International Publication Number 10 May 2007 (10.05.2007) PCT WO 2007/053596 Al (51) International Patent Classification: Andrew [US/US]; 10542 Rancho Carmel Drive, San A61K 31/00 (2006.01) A61K 31/55 (2006.01) Diego, California 92128 (US). LORRAIN, Kym I. A61K 31/195 (2006.01) A61K 31/4535 (2006.01) [US/US]; 5715 Menorca Drive, San Diego, California A61K 31/485 (2006.01) A61P 25/00 (2006.01) 92124 (US). PIRES, Jammieson C. [US/US]; 5942 A61K 31/495 (2006.01) Alleghany Street, San Diego, California 92139 (US). TREUNER, Kai [DEAJS]; 7665 Palmilla Drive, #5204, (21) International Application Number: San Diego, California 92122 (US). PCT/US2006/042426 (74) Agents: LAU, Kawai et al; TOWNSEND AND (22) International Filing Date: 30 October 2006 (30.10.2006) TOWNSEND AND CREW LLP, 12730 High Bluff Drive, Suite 400, San Diego, California 92130 (US). (25) Filing Language: English (81) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of national protection available): AE, AG, AL, AM, AT,AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN, (30) Priority Data: CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, 60/731,947 3 1 October 2005 (31.10.2005) US GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, (71) Applicant (for all designated States except US): BRAIN- LT, LU, LV,LY,MA, MD, MG, MK, MN, MW, MX, MY, CELLS, INC. [US/US]; 10835 Road To The Cure, Suite MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, 150, San Diego, California 92121 (US). RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, (72) Inventors; and TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW (75) Inventors/Applicants (for US only): BARLOW, Car- (84) Designated States (unless otherwise indicated, for every rolee [US/US] ; 510 Torrey Point Road, Del Mar, California kind of regional protection available): ARIPO (BW, GH, 92014 (US). CARTER, Todd A. [US/US]; 10663 Math- GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, ieson Street, San Diego, California 92129 (US). MORSE, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), [Continued on next page] (54) Title: GABA RECEPTOR MEDIATED MODULATION OF NEUROGENESIS Human Neurogenesis Assay: Baclofen + Captopril Neuronal Differentiation (TUJ1) Conc(M) (57) Abstract: The instant disclosure describes methods for treating diseases and conditions of the central and peripheral nervous system by stimulating or increasing neurogenesis. The disclosure includes compositions and methods based on use of a GABA agent, optionally in combination with one or more other neurogenic agents, to stimulate or activate the formation of new nerve cells. European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, — before the expiration of the time limit for amending the FR, GB, GR, HU, IE, IS, IT, LT,LU, LV,MC, NL, PL, PT, claims and to be republished in the event of receipt of RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, amendments GN, GQ, GW, ML, MR, NE, SN, TD, TG). For two-letter codes and other abbreviations, refer to the "G uid Published: ance Notes on Codes and Abbreviations" appearing at the beg in GABARECEPTOR MEDIATED MODULATION OF NEUROGENESIS RELATED APPLICATIONS This application claims benefit of priority from U.S. Provisional Patent Application 60/731,947, filed October 31, 2005, which is hereby incorporated by reference in its entirety as if fully set forth. FIELD OF THE DISCLOSURE The instant disclosure relates to methods for treating diseases and conditions of the central and peripheral nervous system by stimulating or increasing neurogenesis via modulation of gamma-aminobutyrate ("GABA") receptor activity, optionally in combination with another neurogenic agent. The disclosure includes methods based on the application of a GABA modulator and another neurogenic agent to stimulate or activate the formation of new nerve cells. BACKGROUND OF THE DISCLOSURE Neurogenesis is a vital process in the brains of animals and humans, whereby new nerve cells are continuously generated throughout the life span of the organism. The newly born cells are able to differentiate into functional cells of the central nervous system and integrate into existing neural circuits in the brain. Neurogenesis is known to persist throughout adulthood in at least two regions of the mammalian brain: the subventricular zone (SVZ) of the lateral ventricles and the dentate gyrus of the hippocampus. In these regions, multipotent neural progenitor cells (NPCs) continue to divide and give rise to new functional neurons and glial cells (for review Gage 2000). A variety of factors can stimulate adult hippocampal neurogenesis, e.g. adrenalectomy, voluntary exercise, enriched environment, hippocampus dependent learning and anti-depressants (Yehuda 1989, van Praag 1999, Brown J 2003, Gould 1999, Malberg 2000, Santarelli 2003). Other factors, such as adrenal hormones, stress, age and drugs of abuse can negatively influence neurogenesis (Cameron 1994, McEwen 1999, Kuhn 1996, Eisch 2004). Gamma-aminobutyrate (GABA) is a major inhibitory neurotransmitter in the mammalian CNS, which is found in approximately 40% of all neurons. GABA is synthesized primarily by the enzyme glutamate decarboxylase (GAD), which catalyzes the conversion of the excitatory neurotransmitter glutamate to GABA. GABA mediates a wide range of physiological functions, both in the CNS and in external tissues and organs, via binding to GABA receptors. Three GABA receptor subtypes, termed GABA-A, GABA-B, and GABA-C, have been identified on the basis of their structures, as well as their pharmacological and electrophysiological properties. GABA-A receptors are the must abundant subtype of GABA receptor, and are widely distributed throughout the CNS. GABA-A receptors are ionotropic receptors comprised of multiple subunits that form ligand-gated chloride ion channels. Activation of GABA-A receptors results in the passive diffusion of negative chloride ions into the cell, which increases the negative resting membrane potential (creating an inhibitory postsynaptic potential (IPSP)), rendering the cell more resistant to depolarization. In humans, seven classes of GABA-A receptor subunits have been cloned (alpha, beta, gamma, delta, epsilon, pi, and theta subunits), each encoded by a separate gene. In addition, many subunits have multiple isoforms and/or splice variants, giving rise to a large degree of structural diversity (see e.g., Simon et al., J Biol Chem., 279(40):41422-35 (2004)). GABA-A receptors have a pentameric subunit structure, with receptors comprising two alpha, two beta, and one gamma subunit being most commons in the mammalian CNS. GABA-B receptors are widely distributed in the CNS, as well as the autonomic nerves of the PNS. GABA-B receptors are metabotropic, G-protein coupled receptors (GPCRs) of the seven-transmembrane family, and are functionally linked to potassium and/or calcium ion channels. Activation of presynaptic GABA-B receptors inhibits the influx of calcium, resulting in the inhibition of the release of GABA and/or other neurotransmitters by presynaptic neurons. Activation of postsynaptic GABA-B receptors opens potassium channels, resulting in an efflux of potassium out of the cell and an increase in the negative resting membrane potential. The GABA-B mediated response is a 'slow' response that underlies the late phase of the IPSP, whereas the GABA-A mediated response is a 'fast' response that underlies the early phase of the IPSP. GABA- B receptors can also modulate the activity of adenylyl cyclase, resulting in a variety of downstream responses. There are two GABA-B receptor subunits encoded by separate genes, termed GABA-Bl and GABA-B2 (sometimes referred to as GBRl and GBR2, respectively), each of which gives rise to multiple splice variants. GABA-B receptors generally have a heterodimeric subunit composition (B1-B2). GABA-C receptors are ionotropic receptors similar in structure and function to GABA-A receptors, but with a distinct subunit composition, distribution, and pharmacology. GABA-C receptors, like GABA-A receptors, are pentameric ligand-gated chloride ion channels. However, GABA-C receptors are comprised of a distinct subunit type, termed rho subunits, which exist in three isoforms. GABA-C receptors are primarily expressed in the retina, although the mRNA of certain rho subunits is more widely distributed throughout the CNS. Rho subunits have demonstrated the ability to form functional receptors in combination with GABA-A subunits in vitro, suggesting the possibility of additional combinations with unknown structure and function. Citation of the above documents is not intended as an admission that any of the foregoing is pertinent prior art. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicant and does not constitute any admission as to the correctness of the dates or contents of these documents. BRIEF SUMMARY OF THE DISCLOSURE Disclosed herein are compositions and methods for the prophylaxis and treatment of diseases, conditions and injuries of the central and peripheral nervous systems by stimulating or increasing neurogenesis. Aspects of the methods, and activities of the compositions, include increasing or potentiating neurogenesis in cases of a disease, disorder, or condition of the nervous system. Embodiments of the disclosure include methods of treating a neurodegenerative disorder, neurological trauma including brain or central nervous system trauma and/or recovery therefrom, depression, anxiety, psychosis, learning and memory disorders, and ischemia of the central and/or peripheral nervous systems. In other embodiments, the disclosed methods are used to improve cognitive outcomes and mood disorders. In one aspect, methods of modulating, such as by stimulating or increasing, neurogenesis are disclosed.