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United States Patent (10) Patent No.: US 8,883,847 B2 Hellerstein Et Al

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United States Patent (10) Patent No.: US 8,883,847 B2 Hellerstein Et Al USOO8883847B2 (12) United States Patent (10) Patent No.: US 8,883,847 B2 Hellerstein et al. (45) Date of Patent: Nov. 11, 2014 (54) COMPOSITIONS AND METHODS OF FOREIGN PATENT DOCUMENTS TREATMENT USING MODULATORS OF JP A2001-72589 3, 2001 MOTONEURON DISEASES JP A2002-5223.87 T 2002 JP A2003-525854 9, 2003 (75) Inventors: Marc K. Hellerstein, Kensington, CA WO WO 2004/078144 9, 2004 (US); Patrizia A. Fanara, Oakland, CA WO WO 2005/081943 A2 9, 2005 (US) WO WO 2005,115372 12/2005 WO WO 2006/017812 A1 2, 2006 WO WO 2006/091728 A 8, 2006 (73) Assignee: KineMed, Inc., Emeryville, CA (US) WO WO 2007/081910 A2 7, 2007 (*) Notice: Subject to any disclaimer, the term of this OTHER PUBLICATIONS patent is extended or adjusted under 35 U.S.C. 154(b) by 398 days. Argyriou, A.A. et al., 2005. “Vitamin E for prophylaxis against chemotherapy-induced neuropathy: a randomized controlled trial.”. (21) Appl. No.: 11/650,020 Neurology, vol. 64, No. 1, pp. 26-31. Bruce, K.M. et al., 2004, "Chemotherapy delays progression of (22) Filed: Jan. 5, 2007 motor neuron disease in the SOD1 G93A transgenic mouse', vol. 50, No. 3, pp. 138-142. (65) Prior Publication Data Kozhevnikova, E.V. et al., 1999, “Neuroprotective activity of US 2007/0238773 A1 Oct. 11, 2007 angiotensin-converting enzyme inhibitors during cerebral ischemia', Bulletin of Experimental Biology and Medicine, vol. 128, No. 5, pp. 1122-1124. O O Landen, J. et al., 2004, “Noscapine crosses the blood-brain barrier Related U.S. Application Data and inhibits glioblastoma CE Clinical Cancer Research, vol. (60) Provisional application No. 60/756,836, filed on Jan. 10, No. 15. 5, 2006, provisional application No. 60/756,952, filed Landen, J., et al 2002, “Noscapine alters microtubule dynamics in On Jan. 5, 2006. living cells and inhibits the progression of melanoma', vol. 62, No. s 14, pp. 4109-41 14. (51) Int. Cl. Mooraki, A., et al 2005, "Noscapine suppresses angiotensin con A6 IK3I/353 (2006.01) y inhibitors-induced cough', Nephrology, vol. 10, No. A6 IK3I/55 (2006.01) Stubblefield, M.D. et al., 2005, “Glutamine as a Neuroprotective A6IP 25/14 (2006.01) Agent in High-dose Paclitaxel-induced Peripheral Neuropathy: A A6IP 25/6 (2006.01) Clinical and Electrophysiologic Study”. Clinical Oncology, vol. 17. GOIN33/68 (2006.01) No. 4, pp. 271-276. A6 IK3I/35 (2006.01) (Continued) A6 IK3I/4748 (2006.01) CO7D 407/04 (2006.01) A6 IK3I/474 (2006.01) Primary Examiner — Sreeni Padmanabhan A6 IK3I/40 (2006.01) Assistant Examiner — Sahar Javanmard A6 IK 45/06 (2006.01) (74) Attorney, Agent, or Firm — Moran, Lewis & Bockius (52) U.S. Cl. LLP CPC ............ G0IN33/6896 (2013.01); A61 K3I/35 40704(2013.01); (2013.01); A61 K3I/4748 A61K 31/4741 (2013.01); (2013.01); C07D (7) ABSTRACT A61K 31/40 (2013.01); A61K 45/06 (2013.01) The invention disclosed herein describes a novel therapeutic USPC ....................... 514/454: 514/280: 514/211.01 target for motoneuron diseases (altered dynamics of micro (58) Field of Classification Search tubules in neurons); a method for measuring the state of USPC .......... 514/410, 411,422,454, 269.7, 71,90, activity of this therapeutic target in subjects with established, 514/385, 355, 280, 211.01 incipient, or potential motoneuron disease; the discovery of See application file for complete search history. drug agents that modulate neuronal microtubule dynamics in living Subjects with motoneuron diseases; the discovery that (56) References Cited administration of Such agents, alone or in combinations, can provide marked neuroprotective therapy for living Subjects U.S. PATENT DOCUMENTS with motoneuron diseases including delay in Symptoms and 4,818,539 A * 4, 1989 Shaw et al. ................... 424/441 prolongation of survival; and the discovery that monitoring of 5,229,394 A * 7/1993 Salazar-Grueso ............ 514,289 neuronal microtubule dynamics in Subjects with motoneuron 5,780.489 A * 7/1998 Brooks ......................... 514,369 diseases, in response to therapeutic interventions, allows 6,524,629 B1* 2/2003 Christen ....................... 424,752 diagnostic monitoring for optimization of therapeutic regi 7,572,762 B1 8/2009 Spruce et al. 2003. O166670 A1 9, 2003 BrookS-Korn men and strategy for individual Subjects or for drug trials. 2003/0228259 A1 12, 2003 Hellerstein 2006.0020440 A1 1/2006 Hellerstein 2008, OO14267 A1 1/2008 Giordano et al. 8 Claims, 25 Drawing Sheets US 8,883,847 B2 Page 2 (56) References Cited taxanes.” Journal of Biological Chemistry vol. 279, No. 48, pp. 499.40-49947. OTHER PUBLICATIONS Fanara et al., "Stabilization of Hyperdermic Microtubles is Neuroprotective in Mayotrophic Lateral Sclerosis' J. Bio. Chem. Baqiri, R. et al. "Kinesin-2 Differentially Regulates the Anterograde vol. 282, No. 32, pp. 23465-23472, 2007. Axonal Transports of Acetylcholinesterase and Choline Feit. Howard et al., “Is Tubulin a Glycoprotein’?” Biochem Biophys Acetyltransferase in Drosophila', 2006, J. Neurobiology, vol. 66, Res Comm 66:, No. 3, 1975, pp. 920-927. Trojanowski, John Q. et al., “Microtuble-stabilising drugs for therapy No. 4, pp. 378-392. of Alzheimer's disease and other neurodegenerative disorders with Ratner, N. et al. "A Role for Cyclin-Dependant Kinase(s) in the axonal transport impairments.” Expert Opin. Pharmacother: (2005) Modulation of Fast Anterograde Axonal Transport: Effects Defined 6(5):683-686. by Olomoucine and the APC Tumor Suppressor Protein' 1998, J. Wacker, Irene et al., “Microtuble-dependent transport of secretary Neuroscience, vol. 18(19):7717-1726. vesicles visualized in real time with a GFP-tagged secretory protein'. Van Laar, J.M. et al., Tweaking Microtubles to Treat Scleroderma, J. of Cell Science 110, 1453-1463 (1997). PLOS Medicine, (2005) vol. 2, p. 1230-1231. Hino, Mizuki, "Glycosylation of the Alpha and Beta Tubulin by Zeeberg B. et al., 1980, “Exchange of tuburlin dimer into rings in Sialyioligosaccharides”, Zoological Science 20: 709-715 (2003). microtuble assembly-dissasemnly.” Biochemistry vol. 19, No. 22, pp. Galbraith, J.A. et al., “Axonal transport of tubulin and actin.” Journal 5078-5086. of Neurocytology, 2000, vol. 29, pp. 889-911. Fanara, Patrizia et al., 2004, “In vivo measurement of microtuble dynamics using stable isotope labeling with heavy water. Efect of * cited by examiner U.S. Patent Nov. 11, 2014 Sheet 2 of 25 US 8,883,847 B2 CH, COO CH COO Leucine:ina XH-CH,- /-H TA CH, -CH, c / CH, Nii, CH, O ho F.G. 1B U.S. Patent Nov. 11, 2014 Sheet 3 of 25 US 8,883,847 B2 C10 e-R' H H. ROH 18 &Oy ''O18 - CC-R Cc-R SynthesisProtein Vp-R \ / / \ Y NH NH Eno (Free amino acid) (18O labeled c free amino acid) / HN \ (Protein-bound 18O-labeled free amino acid) F.G. 1C U.S. Patent Nov. 11, 2014 Sheet 4 of 25 US 8,883,847 B2 Tubulin 2H-Dimer Tubulin 2H-Polymer H2O -> OO = Dinner - MTPA Flux of Dinner 21 Polymer into Polymer - - - - - - T Polymer + MTPA Time FIG. 2 U.S. Patent Nov. 11, 2014 Sheet 5 Of 25 US 8,883,847 B2 A) 2HO Label followed by Brain Dissection Cytosolic Extract MAP2 antibody High-speed Centrifugation Microtubule fraction Soluble Tubulin Tau antibody TAU Antibody Coupledgel Unbound Pure Tubulin OOut Bound (MAP2- and fraffi CS- fractions) (Tau-fraction) GC-MS Pure Tubulin Pure Tubulin GC-MS GC-MS C) 25 COrtex 25 HippocampuS 20 Dimer - 20 SS -1. SS Dimer E 15 S 15 C o i 10 - POFolymer gs 10 Polymer o (tau-MTs) s (tau-MTs) 5 --- S. Polymer g 5 Polymer (tau-nonassociated (tau-nonassociated 0 MTs) U- O MTs) O 5 10 15 20 25 O 5 10 15 20 25 Time (h) Time (h) FIG 3 U.S. Patent Nov. 11, 2014 Sheet 6 of 25 US 8,883,847 B2 Tau-MTS STOP-MTS (growth cone) (axonal shaft) 5 WT 2 4 SOD1 G93A 3 5 2 1 d O 0 a 6 Tal-MS 6 STOP-MTS (axonal shaft) S. 5 (growth cone) 5 WT 4 SOD1 GA 3 3 2 2 1 1 0 O Ta-Ms STOPMTs g (growth cone) (axonal shaft) s 5 As WT a 4 SOD1 Gig 3 2 e O123456 FIG. 4 U.S. Patent Nov. 11, 2014 Sheet 7 of 25 US 8,883,847 B2 6 S 5 Sl -o- Wild type E. 4 -A- SOD1 G93A C 3 s of 2 6 8 10 12 14 16 18 Age (Weeks) FIG. 5 U.S. Patent Nov. 11, 2014 Sheet 8 of 25 US 8,883,847 B2 -o- Wild type All SOD1 G93A treated (MK801) -A - SOD1 G93A 6 5 5 C -- Wildtype 4 - SOD1 G93A - 3 treated (NoScapine) -- SOD1 G93A 2 1 6 8 10 12 14 16 18 6 5 5 -o- Wildtype 4 SOD1 G93A 5 treated (MK801/NoScapine) 3 -Al SOD1 G93A s i 2 e1 1 6 8 10 12 14 16 18 Age (Weeks) FIG. 6 U.S. Patent Nov. 11, 2014 Sheet 9 of 25 US 8,883,847 B2 WT Tal-MTS (Er SOD1 G93AUntreated S. Co withSOD1 MK801/Noscapine Treated 3 1 FIG. 7 U.S. Patent Nov. 11, 2014 Sheet 11 of 25 US 8,883,847 B2 NMDA-Receptor Antagonists is co,h N 1. co C Honoquinolinic Acid POH, SPO, O C 3. NCO, HN Co, 1 "Co.H OC HN1 co, (R)-AP5 (R)-CPP-ene PBPDa COCC CH, C "AllNH, CH, C.HNbi, MK-8) Memantine Ketamine FOO C iO C Coro H C 1 "co,H L-701,3243 L-689,560 GW196771A2S pH C Ro 25-698 HO C."Olu?) s C Ifenprodil O HO NS OH Co.
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