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(12) United States Patent (10) Patent No.: US 6,284,540 B1 Milbrandt Et Al

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(12) United States Patent (10) Patent No.: US 6,284,540 B1 Milbrandt Et Al USOO628454OB1 (12) United States Patent (10) Patent No.: US 6,284,540 B1 Milbrandt et al. (45) Date of Patent: Sep. 4, 2001 (54) ARTEMIN, A NOVEL NEUROTROPHIC Ross et al., “Gene Therapy in the United States: A Five Year FACTOR Status Report.” Human Gene Therapy, vol. 7:1781-1790, Sep.1996.* (75) Inventors: Jeffrey D. Milbrandt; Robert H. Scheffler et al., “Marrow-mindedness: a perspective on Baloh, both of St. Louis, MO (US) neuropoiesis.” TINS, vol. 22 (8): 348-357, 1999.* Sanberg et al., “Cellular therapeutic approaches for neuro 73) AssigSCC Washingtonashington UniUniversity, ity, St. Louis, MO degenerative disorders.” Proceedings of the 1998 Miami (US) Bio/Technology winter Symposium, Nucleic Acids Sympo sium series No. 38 : 139-142, Feb. 1998.* * Y NotOtice: Subjubject to anyy disclaimer,disclai theh term off thisthi Bowie et al., “Deciphering the message in protein patent is extended or adjusted under 35 Sequences: Tolerance to amino acid Substitution.” Science, U.S.C. 154(b) by 0 days. vol. 247: 1306-1310, Mar. 1990.* Ngo et al., “Computational complexity, protein Structure (21) Appl. No.: 09/220,528 prediction, and the Levinthal Paradox.” The Protein Folding (22) Filed: Dec. 24, 1998 Problem and Tertiary Structure Prediction:491–495, 1994.* Frommel et al., “En estimate on the effect of point mutation Related U.S. Application Data and natural Selection on the rate of amino acid replacement in proteins.” Mol. Evol., vol. 21: 233-257, 1985.* (60) Division of application No. 09/218,698, filed on Dec. 22, 1998, and a continuation-in-part of application No. 09/163, Baloh et al., GFRC3 is an orphan member of the GDNF/ 283, filed on Sep. 29, 1998. neurturin/persephin receptor family, Proc. Natl. Acad. Sci. (60) Provisional application No. 60/108,148, filed on Nov. 12, USA 95:5801–5806 (1998). 1998. Jing et al., GFRC-2 and GFRC-3 Are Two New Receptors for Ligands of the GDNF Family, J. Biol. Chem. (51) Int. Cl. ............................. C12N 5700; C12N 5/08; 272:33111-33117 (1997). C12N 15/63; C12N 15/85; CO7H 21/04 National Cancer Institute, Cancer Genome Anatomy Project, (52) U.S. Cl. ....................... 435/455; 435/320.1; 435/325; GenBank AA533512. 435/366; 435/368; 435/383; 435/384; 536/23.5 National Cancer Institute, Cancer Genome Anatomy Project, (58) Field of Search ............................... 530/350; 514/44; GenBank AA931637. 435/4, 320.1, 5, 29; 536/23.5 Naveilhan et al., Expression and regulation of GFRC3, a (56) References Cited glial cell line-derived neurotrophic factor family receptor, Proc. Natl. Acad. Sci. USA 95:1295–1300 (1998). U.S. PATENT DOCUMENTS Waterston, GenBank AC005038. 5,739,307 4/1998 Johnson, Jr. et al. ............ 536/23.51 Waterston, GenBank AC005051. 5,747,655 5/1998 Johnson, Jr. et al. ............... 530/399 Widenfalk et al., GFRC-3, a protein related to GFRO-1, is expressed in developing peripheral neurons and ensheathing FOREIGN PATENT DOCUMENTS cells, Eur: J. Neurosci. 10:1508–1517 (1998). WO OO/04050 1/2000 (WO). Worby et al., Identification and Characterization of WOOO/O1815 1/2000 (WO). GFRC-3, a Novel Co-receptor Belonging to the Glial Cell Line-derived Neurotrophic Receptor Family, J. Biol. Chem. OTHER PUBLICATIONS 273:3502–3508 (1998). Nishino et al., “GFRa3, a Component of the Artemin Recep tor is Required for Migration and Survival of the Superior * cited by examiner Cervical Ganglion.” Neuron, vol. 23: 725–736, Aug. 1999.* Airaksinen et al., “Review-GDNF Family Neurotrophic Primary Examiner Karen M. Hauda Factor Signaling: Four Masters, One Servant?” Molecular ASSistant Examiner Anne-Marie Baker and Cellular Neuroscience, vol. 13:313–325, 1999.* (74) Attorney, Agent, or Firm-Howell & Haferkamp, L.C. Saarma et al., “Other Neurotrophic Factors: Glial Cell (57) ABSTRACT Line-Derived Neurotrophic Factor (GDNF).” Microscopy Researchand Technique, vol. 45: 292-302, 1999.* A novel growth factor, artemin, which belongs to the GDNF/ Miller et al., “Targeted vectors for gene therapy.” FASEB neurturin/perSephin family of growth factors, is disclosed. Journal, vol. 9:190-199, Feb. 1995.* The human and mouse amino Sequences have been identi Blau et al., “Molecular Medicine Gene Therapy-A novel fied. Human and mouse artemin genomic DNA sequences form of drug delivery.” The New England Journal of Medi have been cloned and Sequenced and the respective cDNA cine, vol. 333 (18): 1204-1207, Nov. 1995.* Sequences identified. In addition, methods for treating Crystal R, “Transfer of Genes to Humans: Early Lessons and degenerative conditions using artemin, methods for detect Obstacles to Success.’ Science, vol. 270: 404-410, Oct. ing artemin gene alterations and methods for detecting and 1995.* monitoring patient levels of artemin are provided. Verma et al., “Gene Therapy-promises, problems, and prospects.” Nature, vol. 389: 239-242, Sep. 1997.* 5 Claims, 39 Drawing Sheets U.S. Patent Sep. 4, 2001 Sheet 5 of 39 US 6,284,540 B1 00|| 00Z 008 U.S. Patent Sep. 4, 2001 Sheet 6 of 39 US 6,284,540 B1 9.InáHz-OL U.S. Patent Sep. 4, 2001 Sheet 11 Of 39 US 6,284,540 B1 i g U.S. Patent Sep. 4, 2001 Sheet 12 of 39 US 6,284,540 B1 0 9 U.S. Patent Sep. 4, 2001 Sheet 13 of 39 US 6,284,540 B1 …ºffset(gebºººeee!!!Ë U.S. Patent Sep. 4, 2001 Sheet 14 of 39 US 6,284,540 B1 J.V.2bot• U.S. Patent Sep. 4, 2001 Sheet 15 Of 39 US 6,284,540 B1 U.S. Patent Sep. 4, 2001 Sheet 16 Of 39 US 6,284,540 B1 U.S. Patent Sep. 4, 2001 Sheet 17 of 39 US 6,284,540 B1 hippocampus oblongatamedulla bthalamic -- :::::::: " nucleus spinal cord thymus peripheral C. human DNA U.S. Patent Sep. 4, 2001 Sheet 18 Of 39 US 6,284,540 B1 six if, FK S3 U.S. Patent Sep. 4, 2001 Sheet 19 Of 39 US 6,284,540 B1 Sciatic view: 8 3. 88. U.S. Patent Sep. 4, 2001 Sheet 20 of 39 US 6,284,540 B1 1000 Figure 7A 800 ||90Jequunu § U.S. Patent Sep. 4, 2001 Sheet 21 of 39 US 6,284,540 B1 1800 1000 U.S. Patent Sep. 4, 2001 Sheet 22 of 39 US 6,284,540 B1 200 ||3OJequunu SuOun?N+HL Figure 7F U.S. Patent Sep. 4, 2001 Sheet 23 Of 39 US 6,284,540 B1 FGRE BA U.S. Patent Sep. 4, 2001 Sheet 24 Of 39 US 6,284,540 B1 FR: 33 U.S. Patent Sep. 4, 2001 Sheet 25 Of 39 US 6,284,540 B1 GE 8) U.S. Patent Sep. 4, 2001 Sheet 26 of 39 US 6,284,540 B1 10 0.8 9C San O.8 O 8 CS S8C. N. 0.2 O.O S N S. & S. U.S. Patent Sep. 4, 2001 Sheet 27 Of 39 US 6,284,540 B1 eige 8 R8 U.S. Patent Sep. 4, 2001 Sheet 28 of 39 US 6,284,540 B1 Z000Z009||000!009€.000€009 009 O97W Sheet 29 of 39 US 6,284,540 B1 O 500 1000 1500 2000 2500 3000 3500 GFRO2-Fo (ng/mL) Figure 9D O 500 1000 1500 2000 2500 3000 3500 GFRo.3-Fo (ng/mL) Figure 9E U.S. Patent Sep. 4, 2001 Sheet 30 of 39 US 6,284,540 B1 O NOTreatment |lllllllllllll N |||||||||||||||| Control GFRO1 GFRO2 GFR03NSSSSS Figure 10A No Treatment N Control GFRO1 GFRO2 GFRO3NS Figure 10B U.S. Patent Sep. 4, 2001 Sheet 31 of 39 US 6,284,540 B1 Ret Ret Ret Figure 11 U.S. Patent Sep. 4, 2001 Sheet 36 of 39 US 6,284,540 B1 --TFT__) US 6,284,540 B1 1 2 ARTEMIN, A NOVEL NEUROTROPHIC member of this family to be discovered, was shown to be FACTOR related to NGF by virtue of the conservation of all six cysteines that form the three internal disulfides of the NGF RELATED APPLICATIONS monomer (Barde, Prog Growth Factor Res 2:237-248, 1990 This application, is a divisional of U.S. application Ser. 5 and Liebrock et al. Nature 341:149-152, 1989). By utilizing No. 09/218,698 filed Dec. 22, 1998, which claims priority to the information provided by BDNF of the highly conserved Provisional Application Serial No. 60/108,148 filed Nov. 12, portions of two factors, additional members (NT-3, NT 4/5) 1998, and a continuation-in-part of application Ser. No. of this neurotrophin family were rapidly found by several groups (Klein, FASEB J 8:738–44, 1994). 09/163,283, filed Sep. 29, 1998. Recently, a new family of neurotrophic factorS has been REFERENCE TO GOVERNMENT GRANT identified whose members are not structurally related to This invention was made with government Support under NGF and other neurotrophins but are structurally similar to NIH Grant Number SRO1-AG13730-03. The government TGF-B. As described in U.S. Pat. No. 5,739,307 and copend has certain rights in this invention. ing application Ser. No. 08/931,858, the known members of 15 this subfamily of the TGF-B superfamily include glial cell BACKGROUND OF THE INVENTION line-derived neurotrophic factor (GDNF), neurturin (NTN), and persephin (PSP). The placement of GDNF, neurturin and (1) Field of the Invention persephin into the same growth factor family, also referred This invention relates generally to trophic or growth to as the GDNF ligand family, is based on the similarities of factors and, more particularly, to a new growth factor, their physical Structures and biological activities. Human artemin, which is a member of the neurturin-persephin persephin has about 40% sequence identity and about 43% GDNF family of growth factors.
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