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(12) Patent Application Publication (10) Pub. No.: US 2007/0208029 A1 Barlow Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2007/0208029 A1 Barlow Et Al US 20070208029A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0208029 A1 Barlow et al. (43) Pub. Date: Sep. 6, 2007 (54) MODULATION OF NEUROGENESIS BY PDE Related U.S. Application Data INHIBITION (60) Provisional application No. 60/729,366, filed on Oct. (75) Inventors: Carrolee Barlow, Del Mar, CA (US); 21, 2005. Provisional application No. 60/784,605, Todd A. Carter, San Diego, CA (US); filed on Mar. 21, 2006. Provisional application No. Kym I. Lorrain, San Diego, CA (US); 60/807,594, filed on Jul. 17, 2006. Jammieson C. Pires, San Diego, CA (US); Kai Treuner, San Diego, CA Publication Classification (US) (51) Int. Cl. A6II 3 L/506 (2006.01) Correspondence Address: A6II 3 L/40 (2006.01) TOWNSEND AND TOWNSEND AND CREW, A6II 3/4I (2006.01) LLP (52) U.S. Cl. .............. 514/252.15: 514/252.16; 514/381: TWO EMBARCADERO CENTER 514/649; 514/423: 514/424 EIGHTH FLOOR (57) ABSTRACT SAN FRANCISCO, CA 94111-3834 (US) The instant disclosure describes methods for treating dis 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 use of (21) Appl. No.: 11/551,667 a PDE agent, optionally in combination with one or more other neurogenic agents, to stimulate or activate the forma (22) Filed: Oct. 20, 2006 tion of new nerve cells. Patent Application Publication Sep. 6, 2007 Sheet 1 of 6 US 2007/0208029 A1 Figure 1: Human Neurogenesis Assay: budilast + Captopril Neuronal Differentiation budilast + Captopril ' ' ' 'Captopril " " " 'budilast 10 Captopril Concentration 10-8.5 10-8.0 10-7.5 10-7.0 10-6.5 10-6.0 10-5.5 10-5.0 10-4.5 10-40 ammammam 10-9.0 10-8.5 10-8-0 10-75 10-7.0 10-6.5 10-6.0 10-5.5 10-50 10-4.5 Conc (M) Ibudilast Concentration Patent Application Publication Sep. 6, 2007 Sheet 2 of 6 US 2007/0208029 A1 Figure 2: Human Neurogenesis Assay: Enoximone + Captopril Neuronal Differentiation (TUJ1) 140 130 Enoximone + Captopril 120 ---. Captopril 110 - - - - EnoximOne 100 90 80 70 60 50 40 30 20 10 of Captopril and Enoximone O Concentration Conc (M) Patent Application Publication Sep. 6, 2007 Sheet 3 of 6 US 2007/0208029 A1 Figure 3: Human Neurogenesis Assay: EnoximOne + Serotonin Neuronal Differentiation 120 EnoximOneU + Serotonin A. 100 ---- Serotonin 90 - - - - EnoximOne 80 70 60 50 40 30 20 10 is Serotonin and Enoximone Concentration 10-8.5 10-8.0 10-7.5 10-7.0 10-6.5 10-6.0 10-5.5 10-5.0 10-4.5 10-40 Conc (M) Patent Application Publication Sep. 6, 2007 Sheet 4 of 6 US 2007/0208029 A1 Figure 4: Human Neurogenesis Assay: Rolipram + Serotonin Neuronal Differentiation (TUJ1) 110 100 Rolipram + Serotonin 90- -- Serotonin p 80 ---. Rolipram 5 O 19, 10-8.0 10-7.5 10-7.0 10-6.5 10-6.0 10-5.5 10-5.0 10-4.5 10-40 Conc (M) Patent Application Publication Sep. 6, 2007 Sheet 5 of 6 US 2007/0208029 A1 Figure 5: Human Neurogenesis Assay: Rolipram + Buspirone Neuronal Differentiation (TUJ1) 110 100 Rolipram + Buspirone 90- - - BuSpirone 80 ----Rolipram 70 60 50 40 30 20 10 -1 St. 10-8.0 10-7.5 10-7.0 10-6.5 10-6.0 10-5.5 10-5.0 10-4.5 10-4.0 Conc (M) Patent Application Publication Sep. 6, 2007 Sheet 6 of 6 US 2007/0208029 A1 Figure 6: Human Neurogenesis Assay: budilast + Candesartan Neuronal Differentiation (TUJ1) 'l Ibudilast Candesartan ---budilast Candesartan Candesartan Concentration 10-8.5 10-8.0 10-7.5 107.0 10-6.5 10-6-0 10-5.5 10-5.0 10-4.5 10-40 10-9.0 10-8-5 10-8.0 10-7.5 10-7.0 10-6.5 10-6.0 10-55 10-50 10-4.5 Conc (M) budilast Concentration US 2007/0208029 A1 Sep. 6, 2007 MODULATION OF NEUROGENESIS BY PDE comprise multiple genes, which give rise to distinct INHIBITION isozymes. For example, the PDE3, PDE6, PDE7, and PDE8 families each comprise at least two genes (3A, 3B; 6A, 6B; RELATED APPLICATIONS 7A, 7B: 8A, 8B), while the PDE1 family comprises at least three genes (1A, 1B, 1C), and the PDE4 family comprises at 0001. This application claims benefit of priority from least four genes (4A, 4B, 4C, 4D). In addition, the majority U.S. Provisional Patent Application 60/729,366, filed Oct. of PDE gene transcripts are Subject to alternative splicing, 21, 2005, 60/784,605, filed Mar. 21, 2006, and 60/807,594, giving rise to multiple isozymes within each family. PDE filed Jul. 17, 2006. All three of these applications are hereby isozymes are differentially expressed in various tissues, cell incorporated by reference as if fully set forth. types, and subcellular locations, and numerous PDE FIELD OF THE DISCLOSURE isozymes have been detected throughout the CNS. 0002 The instant disclosure relates to methods for treat 0006 Citation of the above documents is not intended as ing diseases and conditions of the central and peripheral an admission that any of the foregoing is pertinent prior art. nervous system by stimulating or increasing neurogenesis All statements as to the date or representation as to the via inhibition of cyclic nucleotide phosphodiesterase contents of these documents is based on the information (“PDE) activity, optionally in combination with another available to the applicant and does not constitute any admis neurogenic agent. The disclosure includes methods based on sion as to the correctness of the dates or contents of these the application of an PDE inhibitor and another neurogenic documents. agent to stimulate or activate the formation of new nerve BRIEF SUMMARY OF THE DISCLOSURE cells. 0007 Disclosed herein are compositions and methods for the prophylaxis and treatment of diseases, conditions and BACKGROUND OF THE DISCLOSURE injuries of the central and peripheral nervous systems by 0003) Neurogenesis is a vital process in the brains of stimulating or increasing neurogenesis. Aspects of the meth animals and humans, whereby new nerve cells are continu ods, and activities of the compositions, include increasing or ously generated throughout the life span of the organism. potentiating neurogenesis in cases of a disease, disorder, or The newly born cells are able to differentiate into functional condition of the nervous system. Embodiments of the dis cells of the central nervous system and integrate into exist closure include methods of treating a neurodegenerative ing neural circuits in the brain. Neurogenesis is known to disorder, neurological trauma including brain or central persist throughout adulthood in two regions of the mamma nervous system trauma and/or recovery therefrom, depres lian brain: the subventricular Zone (SVZ) of the lateral Sion, anxiety, psychosis, learning and memory disorders, and Ventricles and the dentate gyrus of the hippocampus. In these ischemia of the central and/or peripheral nervous systems. In regions, multipotent neural progenitor cells (NPCs) continue other embodiments, the disclosed methods are used to to divide and give rise to new functional neurons and glial improve cognitive outcomes and mood disorders. cells (for review Gage 2000). It has been shown that a 0008. In one aspect, methods of modulating, such as by variety of factors can stimulate adult hippocampal neuro stimulating or increasing, neurogenesis are disclosed. The genesis, e.g., adrenalectomy, Voluntary exercise, enriched neurogenesis may be at the level of a cell or tissue. The cell environment, hippocampus dependent learning and anti or tissue may be present in an animal Subject or a human depressants (Yehuda 1989, van Praag 1999, Brown J 2003, being, or alternatively be in an in vitro or ex vivo setting. In Gould 1999, Malberg 2000, Santarelli 2003). Other factors, Some embodiments, neurogenesis is stimulated or increased Such as adrenal hormones, stress, age and drugs of abuse in a neural cell or tissue. Such as that of the central or negatively influence neurogenesis (Cameron 1994, McEwen peripheral nervous system of an animal or human being. In 1999, Kuhn 1996, Eisch 2004). cases of an animal or human, the methods may be practiced 0004 Cyclic adenosine monophosphate (cAMP) and in connection with one or more diseases, disorders, or cyclic guanosine monophosphate (cGMP) are ubiquitous conditions of the nervous system as present in the animal or second messengers that mediate a wide range of processes in human Subject. Thus, embodiments disclosed herein include mammalian cells, including vision, olfaction, platelet aggre methods of treating a disease, disorder, or condition by gation, aldosterone synthesis, insulin secretion, T cell acti administering at least one neurogenesis modulating agent Vation, and Smooth muscle relaxation. Cyclic nucleotide having inhibitory activity against a cyclic nucleotide phos phosphodiesterases (“PDEs”) regulate intracellular levels of phodiesterase (“PDE), hereinafter referred to as a “PDE cAMP and ccjMP by catalyzing their hydrolysis to the agent'. A PDE agent may be formulated or used alone, or in corresponding nucleotide 5'-monophosphates. Over 20 PDE combination with one or more additional neurogenic agents, genes have been cloned, encoding 11 gene families (PDE1 such as another PDE agent or a non-PDE agent. PDE11), which are classified according to sequence homol 0009. The disclosure thus includes a method of using a ogy, as well as the biochemical and pharmacological prop chemical entity as a PDE agent to increase neurogenesis. In erties of the encoded PDEs (e.g., specificity for cAMP Some embodiments, a chemical entity used as an agent is a and/or cGMP, response to modulatory compounds).
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