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United States Patent (19) 11 Patent Number: 5,863,770 Tsui Et Al

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United States Patent (19) 11 Patent Number: 5,863,770 Tsui Et Al USOO586377OA United States Patent (19) 11 Patent Number: 5,863,770 Tsui et al. (45) Date of Patent: Jan. 26, 1999 54). STABLE METEROLOGOUS PROPAGATION Kerem et al., Identification of Mutations in Regions Corre OF CFTR PROTEIN VARLANT CIDNA sponding to the two Putative Nucleotide (ATP)-Binding Folds of the Cystic Fibrosis Gene, Proc. Natl. Acad. Sci. 75 Inventors: Lap-Chee Tsui, Etobicoke; Johanna USA 87:8447-8451 (1990). M. Rommens, Willowdale, both of Green et al., Chromosomal Region of the Cystic Fibrosis Canada Gene in Yeast Artificical Chromosomes: A Model for Human Genome Mapping, Science 250:94-98 (1990). 73 Assignee: HSC Research and Development Cliff et al., Separate Cl Conductances Activated by cAMP Limited Partnership, Canada and Ca" in Cl-Secreting Epithelial Cells, Proc. Natl. Acad. Sci. USA 87:4956-4960 (1990). 21 Appl. No.: 604,488 Welsh, M.J., Abnormal Regulation of Ion Channels in Cystic 22 Filed: Feb. 21, 1996 Fibrosis Epithelia, GFEB.J. 4:2718-2725 (1990). Hyde et al., Structural Model of ATP-Binding Proteins Related U.S. Application Data Associated with Cystic Fibrosis, Multidrug Resistance and Bacterial Transport, Nature 346:362-365 (1990). 60 Division of Ser. No. 30,081, Apr. 12, 1993, which is a Cutting et al., A Cluster of Cystic Fibrosis Mutations in the continuation-in-part of Ser. No. 401,609, Aug. 31, 1989, abandoned, which is a continuation of Ser. No. 399,945, First Nucleotide-Binding Fold of the Cystic Fibrosis Con Aug. 24, 1989, abandoned, which is a continuation of Ser. ductance Regulator Protein, Nature 346:366-369 (1990). No. 396,894, Aug. 22, 1989, abandoned. Slot et al., No Evidence for Expression of the Insulin-Regu 51 Int.nt. Cl.CI. ............................ C12P 21/04; C12P 21/06 latable Glucose Transporter in Endothelial Cells, Nature C12N 15/09; C12N 15/63 346:369-371 (1990). 52 U.S. Cl. ....................... 435/712; 435/69.1; 435/70.1; Dean et al., Multiple Mutations in Highly Conserved Resi 435/711; 435/1723; 435/91.4; 435/320.1; dues are Found in Mildly Affected Cystic Fibrosis Patients, 435/252.3; 435/366; 935/23; 935/71; 935/72; Cell 61:863–870 (1990). 935/70 Wilson, et al., Correction of CD18-Deficient Lymphocytes 58 Field of Search ................................ 435/691.1, 71.1, by Retrovirus-Mediated Gene Transfer, Science 435/70.1, 71.2, 172.1, 172.3, 91.4, 320.1, 248:1413-1416 (1990). 252.3, 366; 935/23.7, 71.72 Schoumacher et al., A Cystic Fibrosis Pancreatic Adenocari noma Cell Line, Proc. Natl. Acad. Sci USA 87:4012-4016 56) References Cited (1990). White et al., A Frame-Shift Mutation in the Cystic Fibrosis U.S. PATENT DOCUMENTS Gene, Nature 344:665–667 (1990). 4,322,274 3/1982 Wilson et al. ...................... 204/180 G Wilson et al., Expression of Human Adenosine Deaminase 4,844,893 7/1989 Honsik et al. ....... ... 424/85.8 in Mice Reconstituted with Retrovirus-Transduced Ham 4,847,201 7/1989 Kaswasaki et al. ...................... 435/70 atopoietic Stem Cells, Proc. Natl. Acad. Sci. USA 4,853,331 8/1989 Hernstadt et al. ... 435/252.1 87:439–443 (1990). 4,861,589 8/1989 Ju .............................................. 424/93 4,861,719 8/1989 Miller ............... ... 435/236 Boat et al., Cystic Fibrosis in The Metabolic Basis of 4,868,116 9/1989 Morgan et al. .. 435/240.2 Inherited Disease, vol. II, (Scriver et al., eds.) McGraw-Hill 4,980,286 12/1990 Morgan et al. .. ... 435/172.3 Information Services Company, N.Y., N.Y., pp. 2649-2679 5,240,846 8/1993 Collins et al. ....................... 435/240.1 (1989). FOREIGN PATENT DOCUMENTS (List continued on next page.) 0 226288 6/1987 European Pat. Off. ... ... 1/68 Primary Examiner Stephanie W. Zitomer 0 288 299 10/1988 European Pat. Off. ... ... 1/68 Attorney, Agent, or Firm-Bell Seltzer Intellectual Property 0 446 017 9/1991 European Pat. Off. ..................... 5/12 Law Group of Alston & Bird LLP OTHER PUBLICATIONS 57 ABSTRACT Zielenski et al., Genomic DNA Sequence of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) A modified DNA sequence encoding full length cystic Gene, Genomics 10:214–228 (1991). fibrosis transmembrane conductance regulator protein is Drum et al., Correction of the Cystic Fibrosis Defect in Vitro provided to facilitate propagation and/or expression of the by Retrovirus-Mediated Gene Transfer, Cell 62:1227–1233 protein in living cells and in particular, bacterial cells. The (1990). modified DNA sequence comprises at least one of the 13 Quinton, P.M., Cystic Fibrosis: A Disease in Electrolyte base pair repeat of eXon 6b of the normal gene encoding the Transport, FASEB.J. 4:2709–2717 (1990). conductance regulator protein, as one or more normal nucle The Cystic Fibrosis Genetic Analysis Consortium, World otides of the 13 base repeat substituted with an alternate wide Survey of the AF508 Mutation-Report from the Cystic nucleotide which, however, continues to code for the cor Fibrosis Genetic Analysis Consortium, Am. J. Hum. Genet. responding normal amino acid. Mammalian cells transferred 47:354-359 (1990). with a vector containing the modified DNA sequence Venglarik et al., A Simple ASSay for Agonist-Regulated Cl enhances chlorine conductance through the cell wall and K Conductances in Salt-Secreting Epithelial Cells, Am. J. Physiol. 259:C358-C364 (1990). 5 Claims, 20 Drawing Sheets 5,863,770 Page 2 OTHER PUBLICATIONS Cheng et al., Increased Sulfation of Glycoconjugates by Cultured Nasal Epithelial Cells from Patients with Cystic Sanbrook et al., Oligonucleotide-Mediated Mutagenesis in Fibrosis, J. Clin. Invest. 84:68–72 (1989). Molecular Cloning, A Laboratory Manual, 2nd Ed., Cold Jetten et al., Persistence of Abnormal Chloride Conductance Spring Harbor Press, Cold Spring Harbor, NY, pp. Regulation in Transformed Cystic Fibrosis Epithelia, Sci 15.51–15.80 (1989). ence 244:1472–1475 (1989). Fulton et al., A 12 Megabase Restriction Map at the Cystic Landry, et al., Purification and Reconstitution of Chloride Fibrosis Locus, Nucleic Acids Research 17(1):271-284 Channels from Kidney and Trachea, Science 244: 1469-1472 (1989). (1989). Dean et al., Approaches to Localizing Disease Genes as Drumm et al., Physical Mapping of the Cytic Fibrosis Applied to Cystic Fibrosis, Nucleic Acids Research Region by Pulsed-Field Gel Electrophoresis, Genomics 18(2):345-350 (1989). 2:346–354 (1988). Rommens et al., Physical Localization of Two DNA Markers Poustka et al., A Long-Range Restriction Map Encompass Closely Linked to the Cystic Fibrosis Locus by Pulsed-Field ing the Cystic Fibrosis Locus and Its Closely Linked Genetic Gel Electrophoresis, Am. J. Hum. Genet. 45:932-941 Markers, Genomics 2:337-345 (1988). (1989). Tsui et al., Progress Towards Cloning the Cystic Fibrosis Kerem et al., DNA Marker Haplotype Association with Gene, Phil. Trans. R. Soc. Lond. B319:263-273 (1988). Pancreatic Sufficiency in Cystic Fibrosis, Am. J. Hum. Rommens et al., Genetic and Physical Mapping of the Genet. 44:827-834 (1989). Chromosomal Region Containing the Cystic Fibrosis Locus, Estivil et al., Isolation of a New DNA Marker in Linkage Am. J. Hum. Genetics 43(3 Suppl.):A199) 1988). Disequilibrium with Cystic Fibrosis, Situated Between J3.11 Rommens et al., Identification and Regional Localization of (D7S8) and IRP. Am. J. Hum. Genet. 44:704–710 (1989). DNA Markers on Chromosome 7 for the Cloning of the Iannuzzi et al., Isolation of Additional Polymorphic Clones Cystic Fibrosis Gene, Am. J. Hum. Genet. 43:645-663 from the Cystic Fibrosis Region, Using Chromosome Jump (1988). ing from D7S8, Am. J. Hum. Genet. 44:695–703 (1989). Farrall et al., Recombinations Bewteen IRP and Cystic Beaudet et al., Linkage Disequilibrium, Cystic Fibrosis and Fibrosis, Am. J. Hum. Genet. 43:471-475 (1988). Genetic Counseling, Am. J. Hum. Genet. 44.319-326 Dean, M., Molecular and Genetic Analysis of Cystic Fibro (1989). sis, Genomics 3:93-99 (1988). Smith et al., Cystic Fibrosis: Diagnostic Testing and the Riordan et al., Molecular Studies of Cultured Epithelial Search for the Gene, Clin. Chem. 35/7(B):B17-B20 (1989). Cells from the Sweat Gland in Cellular and Molecular Basis Jensen et al., Chloride Channel Expression in Cultures of of Cystic Fibrosis, (G. Mastella and P.M. Quinton, Eds.) San Sweat Gland Epithelial Cells in Cystic Fibrosis, J. Cell. Biol. Francisco Press, Inc. San Francisco, CA, pp. 416–424 107(6):139a, Abstract No. 788 (1989). (1988). Orr et al., In Vivo and In Vitro Phosphorylation of Apical Reddy et al., Electrical properties of Cultured Reabsorptive Membrane Proteins of the T-84 Colonic Epithelial Cell Sweat Duct Cells from Normal and Cystic . in Cellular Line, J. Cell Biol. 107(6)493a, Abstract No. 2776 (1989). and Molecular Basis of Cystic Fibrosis (G. Mastella and Willumsen et al., Activation of an Apical CI Conductance by P.M. Quinton, Eds.) San Francisco Press, Inc., San Fran Ca'" Ionophores in Cystic Fibrosis Airway Epithelia, Am. J. cisco, CA, pp. 383-393 (1988). Physiol. 256:C226–C233 (1989). Short et al., 2, ZAP: A Bacteriophage 2 Expression Vector Chen et al., A cAMP-Regulated Chloride Channel in Lym with In Vivo Excision Properties, Nucleic Acids Research 16(15):7583–7600 (1988). phocytes That is Affected in Cystic Fibrosis, Science Reddy et al., Retention of Basic Electrophysiologic Proper 243:657–660 (1989). ties by Human Sweat Duct Cells in Primary Culture, In Vitro Tabcharani et al., Bicarbonate Permeabiltiy of the Out Cellular & Developmental Biology 24(9):905–910 (1988). wardly Rectifying Anion Channel, J. Membrane Biol. Dodge, J.A., Implications of the New Genetics for Screening 112:109–122 (1989). for Cystic Fibrosis, The Lancet:672–673 (1988). Scholte et al., Immortalization of Nasal Polyp Epithelial Wilson et al., Correction of the Genetic Defect in Hepato Cells from Cystic Fibrosis Patients, Experimental Cell cytes from the Watanabe Heritable Hyperlipidemic Rabbit, Research 182:559–571 (1989).
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