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(12) United States Patent (10) Patent No.: US 9,592.288 B2 Schultz Et Al

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(12) United States Patent (10) Patent No.: US 9,592.288 B2 Schultz Et Al USO09592288B2 (12) United States Patent (10) Patent No.: US 9,592.288 B2 Schultz et al. (45) Date of Patent: Mar. 14, 2017 (54) DIRECTED DIFFERENTATION OF (56) References Cited OLGODENIDROCYTE PRECURSOR CELLS TO A MYELINATING CELL FATE U.S. PATENT DOCUMENTS 7.301,071 B2 * 1 1/2007 Zheng .................. CO7K 14,415 (75) Inventors: Peter Schultz, La Jolla, CA (US); Luke 435/320.1 Lairson, San Diego, CA (US); Vishal 2003,0225.072 A1 12/2003 Welsh et al. 2006/0258735 A1 11/2006 Meng et al. Deshmukh, La Jolla, CA (US); Costas 2009. O1552O7 A1 6/2009 Hariri et al. Lyssiotis, Boston, MA (US) 2010, O189698 A1 7, 2010 Willis (73) Assignees: The Scripps Research Institute, La FOREIGN PATENT DOCUMENTS Jolla, CA (US); IRM LLC, Hamilton WO 2009/068668 A1 6, 2009 (BM) WO 2009,153291 A1 12/2009 (*) Notice: Subject to any disclaimer, the term of this OTHER PUBLICATIONS patent is extended or adjusted under 35 U.S.C. 154(b) by 445 days. Mendes et al. “Classical immunomodulatory therapy in multiple sclerosis' Arq Neuropsiquiatr, 2011, vol. 69, No. 3, pp. 536-543.* The TMA. “Animal Models to Study NMO and TM, Nov. 23, (21) Appl. No.: 13/985,342 2015. https://myelitis.org/animal-models-to-study-nmo-and-tim?, printed Jul. 14, 2016, pp. 1-7.* Tian et al. “Neuropathic Pain in Animal Models of Nervous System (22) PCT Fed: Feb. 17, 2012 Autoimmune Diseases' Mediators of Inflammation, 2013, pp. 1-13. Kraker et al. “Autoimmune Neuromuscular Disorder'. Current (86) PCT No.: PCT/US2012/O25712 Neuropharmacology, 2011, vol. 9, pp. 400-408.* Lehmann et al. "Pathogenesisi and treatment of immune-mediated S 371 (c)(1), neuropathies' Therapeutic Advances in Neurological Disorders, (2), (4) Date: Oct. 18, 2013 2009, vol. 2, issue 4, pp. 261-281.* Walgaard et al. "Emerging drugs for Guillain-Barre syndrome' PCT Pub. No.: WO2O12A112933 Expert Opinion of Emerging Drugs, Feb. 25, 2011, vol. 16, issue 1. (87) pp. 105-120.* PCT Pub. Date: Aug. 23, 2012 Collongues et al. “Current and future treatment approaches for neuromyelitis optica. Therapeutic Advances in Neurological Dis orders, 2011, vol. 4, issue 2, pp. 111-121.* (65) Prior Publication Data Oh et al. Treatment of HTLV-1-Associated Myelopathy/Tropical US 2014/OO38949 A1 Feb. 6, 2014 Spastic Paraparesis: Towards Rational Targeted Therapy, Neurol Clin., 2008, vol. 26, issue 3, pp. 781-796 (printed as 1-15).* Alexander et al. "Acute disseminating encephalomyelitis: Treatment guidelines' Ann Indian Acad Neurol, 2011, vol. 14, suppl1, S60 Related U.S. Application Data S64 (printed as pp. 1-12).* Chang et al., “Premyelinating Oligodendrocytes in Chronic Lesions (60) Provisional application No. 61/444,666, filed on Feb. of Multple Sclerosis.” N Engl J Med, 2002, vol. 346, 165. 18, 2011. Chari et al., “Efficient Recolonisation of Progenitor-Depleted Areas of the CNS by Adult Oligodendrocyte Progenitor Cells.” Glia, 2002, 37: 307-313. (51) Int. C. Chariet al., “Dysfunctional Oligodendrocyte Progenitor Cell (OPC) A6 IK3I/545 (2006.01) Populations May Inhibit Repopulation of OPC Depleted Tissue.” J. A6 IK3I/35 (2006.01) Neurosci Res, 2003, 73: 787-793. A6 IK3I/37 (2006.01) A6 IK3I/38 (2006.01) (Continued) A6 IK 3/40 (2006.01) Primary Examiner — Kendra D Carter A6 IK 3/439 (2006.01) (74) Attorney, Agent, or Firm — Kilpatrick Townsend & A 6LX 39/395 (2006.01) Stockton LLP A6 IK 38/2 (2006.01) (52) U.S. C. (57) ABSTRACT CPC ........ A61K 39/3955 (2013.01); A61 K3I/I35 The present invention provides methods of inducing differ (2013.01); A61 K3I/137 (2013.01); A61 K entiation of oligodendrocyte progenitor cells to a mature 3 1/138 (2013.01); A61K 31/40 (2013.01); myelinating cell fate with a neurotransmitter receptor modu A61K 31/439 (2013.01); A61K 3.1/5415 lating agent. The present invention also provides methods of (2013.01); A61K 38/215 (2013.01) stimulating increased myelination in a subject in need (58) Field of Classification Search thereof by administering said neurotransmitter receptor CPC .............. A61K 3.1/5415: A61K 31/135; A61 K modulating agent. Methods of treating a Subject having a 3 1/137; A61K 31/138: A61K 31/40: demyelinating disease using a neurotransmitter receptor A61K 31/439; A61K 38/215: A61 K modulating agent are also provided. 39/3955 See application file for complete search history. 14 Claims, 52 Drawing Sheets US 9,592.288 B2 Page 2 (56) References Cited tion'. International Review of Neurobiology, 2009, vol. 07, pp. 295-312, DOI: 10.1016. Butt et al., “Neurotransmitter-Mediated Calcium Signalling in OTHER PUBLICATIONS Oligodendrocyte Physiology and Pathology.” Sep. 2006, Wiley InterScience, pp. 665-675. Chong et al., “Tapping into the glial reservoir: cells committed to Bangham et al., HTLV-1-associated myelopathy?tropical spastic remaining uncommitted,” J Cell Biol 2010, 188(3), pp. 305-312. paraparesis. Nature Reviews, Article No. 15012, Published online: De Angelis et al., “Muscarinic Receptor Subtypes as Potential doi:10 1038/nrpd.2015.12, 16 pages, Jun. 18, 2015. Targets to Modulate Oligodendrocyte Progenitor Survival, Prolif Guerreiro et al., Levels of serum chemokines discriminate clinical eration, and Differentiation, Dev Neurobiol, 2012, 72: 713-728. myelopathy associated with human T lymphotropic virus type 1 Gobert et al., "Convergent functional genomics of oligodendrocyte (HTLV-1)/tropical spastic paraparesis (HAM/TSP) disease from differentiation identifies multiple autoinhibitory signaling circuits.” HTLV-1 carrier state. Clinical and Experimental Immunology, Molecular and Cellular Biology, 2009, 29:1538. 145:296-301, 2006. Joubert et al., "Chemical inducers and transcriptional markers of Linker and Lee, Models of autoimmune demyelination in the central oligodendrocyte differentiation.” Journal of Neuroscience Research, nervous system: on the way to translational medicine. Experimental 2010, 88: 2546-2557. & Translational Stroke Medicine, 1(5):10 pages, 2009. Kremer et al., “The Complex World of Oligodendroglial Differen Mayo et al., The Innate immune system in demyelinating disease. tiation Inhibitors.” Ann Neurol, 2011, 69: 602-618. Immunol Review, 248(1): 170-187, 2012. Kuhlmann et al., “Differentiation block of oligodendroglia progeni Merrill. In Vitro and In Vivo pharmacological models to access tor cells as a cause for remyelination failure in chronic multiple demyelination and remyelination. Neuropsychopharmacology sclerosis, Brain, 2008, 131, 1749-1758. Reviews, 34:55-73, 2009. Patel et al., “Mediators of oligodendrocyte differentiation during Rangachari and Kuchroo. Using EAE to better understand prin remyelination.” FEBS Lett, 2011, 585, 3730-3737. ciples of immune function and autoimmune pathology. J. Autoim Stevens et al., “Adenosine: A Neuron-Glial Transmitter Promoting mun., 45:31-39, 2013. Myelination in the CNS in Response to Action Potentials.” Neuron, Reeves and Swenson, Disorders of the Nervous System. Chapter 23, Dec. 2002, vol. 36(5), pp. 855-868. “Demyelinating diseases of the nervous system.” reprinted from the Wolswijk, "Chronic Stage Multiple Sclerosis Lesions Contain a internet: http//www.dartmouth.edu/~dons/part3/chapter 23.htm Relatively Quiescent Population of Oligodendrocyte Precursor Apr. 27, 2016, 7 pages. Cells,” J. Neurosci, 1998, 18(2), pp. 601-609. Spalice et al., Clinical and pharmacological aspects of inflammatory PCT application No. PCT/US 12/25712, International Search Report demyelinating diseases in childhood: An update. Current and Written Opinion, 6 pages. Neuropharmacology, 8:135-148, 2010. Deshmukh et al., “A regenerative approach to the treatment of Steinman, Assessment of animal models for MS and demyelinating multiple sclerosis.” Nature, Oct. 2013, vol. 502(7471), pp. 327-332, disease in the design of rational therapy. Neuron, 24:511-5.14, 1999. DOI: 10.1038/nature 12647. Swanborg, Short Analytical Review. Animal models of human Stangel et al., “Remyelination Strategies: New Advancements disease. Experimental Autoimmune encephalomyelitis in rodents as Toward a Regenerative Treatment in Multiple Sclerosis.” Current a model for human demyelinating disease. Clinical Immunology Neurology and Neuroscience Reports, May 2006, vol. 6(3), pp. and Immunopathology, 77(1):4-13, 1995. 229-235. Khoury et al., “A Randomized Controlled Double-Masked Trial of EP Patent Application No. 12 74.7134, Supplementary Search Albuterol Add-on Therapy in Patients With Multiple Sclerosis.” Report, Jun. 18, 2014, 3 pages. Arch Neurol. 2010:67(9): 1055-1061. Magnaghi et al., “Novel Pharmacological Approaches to Schwann cells as Neuroprotective Agents for Peripheral Nerve Regenera * cited by examiner U.S. Patent Mar. 14, 2017. Sheet 1 of 52 US 9,592.288 B2 Fig. IA 1.s K f -o- -N s a r Ceaste; Esq: 8 NYf f s-N- 1SF Berztropine: ECsas 250 V rifluoperazine: Eso's 30 M 1s s!2- (----->-YN-Y-di loh -N Safeter: Coxe is - OutSa - S-N-ro a s SSR 33: Cses 8 BW U.S. Patent Mar. 14, 2017 Sheet 2 of 52 US 9,592.288 B2 Fig. IB w ax (Easte (xx (SER 335 rir rifluropera zine - Carbetapentarie A -- Benztropine ? xx Safetail o re- compound tail U.S. Patent Mar. 14, 2017. Sheet 3 of 52 US 9,592.288 B2 Fig. 2A $8 S Š S Š 8 y 4: Carbapentane Sr. 5: Cerasire 6: GBR12935 & U.S. Patent Mar. 14, 2017 Sheet 4 of 52 US 9,592.288 B2 Fig. 2B-C MBP qRT PCR U.S. Patent Mar. 14, 2017 Sheet S of 52 US 9,592.288 B2 ?uequadeque0 55WIRT U.S. Patent Mar. 14, 2017 Sheet 6 of 52 US 9,592.288 B2 OSWICI **** U.S. Patent Mar. 14, 2017. Sheet 7 of 52 US 9,592.288 B2 Fig. 5A Mycophenolate 3. -- - Weisis: H Mycopieiolate E. , 3 S is 8 it 3 SS F 18 is 324 SS 8. Days U.S. Patent Mar. 14, 2017. Sheet 8 of 52 US 9,592.288 B2 Fig. 5B-C B. Benzatropine 3. 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