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(12) United States Patent (10) Patent No.: US 9,084.825 B2 Montefeltro Et Al

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(12) United States Patent (10) Patent No.: US 9,084.825 B2 Montefeltro Et Al USOO9084825B2 (12) United States Patent (10) Patent No.: US 9,084.825 B2 Montefeltro et al. (45) Date of Patent: Jul. 21, 2015 (54) COMPOSITIONS AND METHODS FOR THE FOREIGN PATENT DOCUMENTS TREATMENT OF PARKINSON DISEASE BY WO WO 88,09810 A1 12, 1988 THE SELECTIVE DELVERY OF WO WO 89,10134 A1 11, 1989 OLGONUCLEOTDE MOLECULESTO WO WO 97.2627O A2 7/1997 SPECIFIC NEURON TYPES WO WO 2007/050789 * 5/2007 WO WO 2007/107789 A2 9, 2007 WO WO 2009,079.399 A2 6, 2009 (71) Applicant: nife Therapeutics, S.L., Armilla, WO WO 2009,079790 A1 T 2009 Granada (ES) WO WO 2011/087804 A2 T 2011 WO WO 2011, 131693 * 10/2011 (72) Inventors: Andrés Pablo Montefeltro, Barcelona WO WO 2011, 131693 A2 10/2011 (ES); Gabriel Alvarado Urbina, WO WO 2012/027713 A2 3, 2012 Nepean (CA); Analia Bortolozzi OTHER PUBLICATIONS Biassoni, Barcelona (ES); Francesc Wersinger et al (FASEB J., vol. 17, pp. 2151-2153 (2003)).* Artigas Pérez, Barcelona (ES); Miquel Wersinger etal (Neuroscience Lett., vol. 340, pp. 189-192 (2003)).* Vila Bover, Barcelona (ES); Maria del Negus etal (J. Pharmacol. & Exp. Therapeutics, vol. 291 No. 1, pp. Carmen Carmona Orozco, Terrassa 60-69 (1999)).* (ES) Gardner et al (Neuropharm. vol. 51, pp. 993-1003 (2006)).* Silva et al (Organic Lett., vol. 9, No. 8, pp. 1433-1436 (2007)).* (73) Assignee: n life Therapeutics, S.L., Granada (ES) Altschul., S.F., et al., “Basic Local Alignment Search Tool.” J. Mol. Biol. 2 15:403-410, Academic Press Limited, England (1990). Beaucage S.L. and Iyer, R.P. “The Functionalization of (*) Notice: Subject to any disclaimer, the term of this Oligonucleotides Via Phosphoramidite Derivatives.” Tetrahedron patent is extended or adjusted under 35 49(10): 1925-1693, Pergamon Press Ltd., England (1993). U.S.C. 154(b) by 0 days. Bolden-Watson, C. and Richelson, E., “Blockade by newly-devel oped antidepressants of biogenic amine uptake into rat brain synaptosomes.” Life Sciences 52:1023-1029, Pergamon Press Ltd., (21) Appl. No.: 14/065,024 England (1993). Crooke, S.T., et al., “Pharmacokinetic Properties of Several Novel (22) Filed: Oct. 28, 2013 Oligonucleotide Analogs in mice.” The Journal of Pharmacology and Experimental Therapeutics 277(2):923-937. The American (65) Prior Publication Data Society for Pharmacology and Experimental Therapeutics, United States (1996). US 2014/O12O158A1 May 1, 2014 Doxakis, E., “Post-transcriptional Regulation of O- Synuclein Expression by mir-7 and mir-153.” J. Biol. Chem. 285(17): 12726 12734. The American Society for Biochemistry and Molecular Biol Related U.S. Application Data ogy, Inc., United States (2010). Egholm, M., et al., “PNA hybridizes to complementary (60) Provisional application No. 61/719.284, filed on Oct. oligonucleotides obeying the Watson-Crick hydrogen-binding 26, 2012. rules.” Nature 365:566-568, Nature Publishing Group, England (1993). Hélène, C., "The anti-gene strategy: control of gen expression by (30) Foreign Application Priority Data triplex-forming-oligonucleotides.” Anti-Cancer Drug Design 6:569 Oct. 26, 2012 (EP) ..................................... 12382414 584, Macmillan Press Ltd., United States (1991). (Continued) (51) Int. Cl. A6 IK 47/48 (2006.01) Primary Examiner — Jane Zara A 6LX3L/705 (2006.01) (74) Attorney, Agent, or Firm — Sterne, Kessler, Goldstein (52) U.S. Cl. & FOX PLLC CPC ....... A61 K47/48023 (2013.01); A61 K3I/7105 (2013.01); A61 K47/481 (2013.01) (57) ABSTRACT (58) Field of Classification Search The invention provides a conjugate comprising (i) a selectiv USPC ............ 424/9.19.2, 450; 435/6, 91.1, 91.31, ity agent which binds specifically to one or more neurotrans 435/458, 6.1, 455; 514/1, 2, 44; 536/23.1, mitter transporters selected from the group consisting of a 536/24.5 dopamine transporter (DAT), serotonin transporter (SERT) or See application file for complete search history. a norepinephrine transporter (NET) and (ii) a nucleic acid capable of specifically binding to a target molecule which is (56) References Cited expressed in the same cell as the neurotransmitter transporter wherein said target molecule is C-synuclein or the mRNA U.S. PATENT DOCUMENTS encoding C-synuclein. The conjugates of the present inven 5,176,996 A 1/1993 Hogan et al. tion are useful for the delivery of the nucleic acid to a cell of 5,256,775 A 10, 1993 Froehler interest and thus, for the treatment of diseases which require 5,264,564 A 11/1993 Matteucci 2010/0221735 A1* 9/2010 Youdim et al. .................... 435/6 a down-regulation of the protein encoded by the target nucleic 2012/01299.12 A1 5/2012 Mouradian et al. acid as well as for the delivery of imaging agents to the cells 2012/0322991 A1 12/2012 Montefeltro et al. for diagnostic purposes. 2014/OOO5252 A1* 1/2014 Bennett et al. .............. 514.f44 A 2014/0315795 A1 10/2014 Carmona Orozco et al. 15 Claims, 6 Drawing Sheets US 9,084.825 B2 Page 2 (56) References Cited Oney, S., et al., “Antidote-Controlled Platelet Inhibition Targeting von Willebrand Factor with Aptamers.” Oligonucleotides 17:265 274, Mary Ann Liebert, Inc., United States (2007). 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Letsinger, R.L., et al., “Cholesteryl-conjugated oligonucleotides: Svinarchuk, F.P. et al., “Inhibition of HIV proliferation in MT-4 cells Synthesis, properties and activity as inhibitors of replication of by antisense oligonucleotide conjugated to lipophilic groups.” human immunodeficiency virus in cell culture.” Proc Natl Acad Sci Biochimie 75:49-54, Société française de biochimie et biologie USA 86:6553-6556, National Academy of Sciences, United States moléculaire/Elsevier, France (1993). (1989). Thompson, J.D., et al., "Clustal W: improving the sensitivity of Liu, Y., et al., “Membrane trafficking of neurotransmitter transporters progressive multiple sequence alignment through sequence weight in the regulation of synaptic transmission.” Trends Cell Biol ing, position-specific gap penalties and weight matrix choice.” 9(9):356-363, Elsevier Science Ltd., England (1999). 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