Chemistry: analytical and immunological testing – Halogen containing – In aqueous solution
Patent
1993-12-09
1995-07-18
Robinson, Douglas W.
Chemistry: analytical and immunological testing
Halogen containing
In aqueous solution
435 63, 514 47, 514263, 514264, 514267, 536 2613, G01N 3300
Patent
active
054340861
ABSTRACT:
Cystic fibrosis (CF), a lethal genetic disease associated with a defect in Cl transport, is caused by mutations in the gene coding for cystic fibrosis transmembrane conductance regulator (CFTR). Surprisingly, not only wild type CFTR, but several naturally-occurring CFTR mutants carrying a defect in the first nucleotide binding fold (NFB1) all expressed cAMP-activatable Cl currents. Treatment of the CFTR mutants with appropriate concentrations of methylxanthine phosphodiesterase inhibitor (which increases cAMP levels) activated Cl conductance to near wild type levels. The present invention thus provides a new avenue for treating cystic fibrosis by the administration of therapeutically effective amounts of compounds which elevate cAMP levels. Dosage and patient responsiveness to treatment, as well as relative efficacies of the compounds being or to be administered can also be determined in accordance with the methods of present invention.
REFERENCES:
patent: 5240846 (1993-08-01), Collins et al.
patent: 5366977 (1994-11-01), Pollard et al.
Boat et al.(I), "Cystic Fibrosis," Ch. 108 in Metabolic Basis of Inherited Disease, McGraw-Hill, New York, 1989, pp. 2649-2680.
Cutting et al., "A Cluster of Cystic Fibrosis Mutations in the First Nucleotide-Binding Fold of the Cystic Fibrosis Conductance Regulator Protein," Nature, 366-369 (1990).
Kerem et al. (I), "The Relationship Between Genotype and Phenotype in Cystic Fibrosis--Analysis of the Most Common Mutations(.DELTA.F.sub.508)," N. Engl. J. Medicine, 323(22), 1517-1522 (1990).
Osborne et al., "A Mutation in the Second Nucleotide Binding Fold of the Cystic Fibrosis Gene," Am. J. Hum. Genetics, 48, 6089-6122 (1991).
White et al., "A Frame-Shift Mutation in the Cystic Fibrosis Gene," Nature, 344, 665-667 (1990).
Ianuzzi et al., "Two Frameshift Mutations in the Cystic Fibrosis Gene," Am. J. Hum. Genetics, 48, 227-231 (1991).
Dean et al., "Multiple Mutations in Highly Conserved Residues Are Found in Mildly Affected Cystic Fibrosis Patients," Cell, 61, 863-870 (1990).
Boat et al. (II), "Human Respiratory Tract Secretions," Arch. Biochem. Biophys., 177, 95-104 (1976).
Kerem et al. (II), "Identification of the Cystic Fibrosis Gene: Genetic Analysis," Science, 245, 1073-1080 (1989).
Kobayashi et al., "Benign Missense Variations in the Cystic Fibrosis Gene," Am. J. Hum. Genetics, 47, 611-615 (1990).
Kerem et al. (III), "Another Single Amino Acid Deletion in the Putative ATP-Binding Domain of the Cystic Fibrosis Gene Product," Proc. Nat. Acad. Sci. USA, 87, 8447-8451 (1990).
Riordan et al., "Identification of the Cystic Fibrosis Gene: Cloning and Characterization of Complementary DNA," Science, 245, 1066-1073 (1989).
Rommens et al. (I), "Identification of the Cystic Fibrosis Gene: Chromosome Walking and Jumping," Science, 245, 1059-1065 (1989).
Schoumacher et al. (I), "A Cystic Fibrosis Pancreatic Adenocarcinoma Cell Line," Proc. Nat. Acad. Sci. USA, 87, 4012-4016 (1990).
Smith, "In Vitro Mutagenesis," Ann. Rev. Genetics, 19, 423-462 (1985).
Strong et al., "Cystic Fibrosis Gene Mutation in Two Sisters with Mild Disease and Normal Sweat Electrolyte Levels," N. Engl. J. Medicine, 325, 1630-1634 (1991).
Taussig, "Cystic Fibrosis: An Overview," in Cystic Fibrosis, Taussig ed., Thiene-Stralton, New York, 1984, pp. 1-9.
Ten Kate, "Carrier Screening for Cystic Fibrosis and Other Autosomal Recessive Diseases," Am. J. Hum. Genetics, 47, 359-361 (1990).
Feinberg et al., "A Technique for Radiolabelling DNA Restriction Endonuclease Fragments to High Specific Activity," Anal. Biochem., 132, 6-13 (1983).
Nicholson et al., "Differential Modulation of Tissue Function and Therapeutic Potential of Selective Inhibitors of Cyclic Nucleotide Phosphodiesterase Isozymes," Trends in Pharmacological Sciences, 12, 19-27 (1991).
Beavo et al., "Primary Sequence of Cyclic Phosphodiesterase Isozymes and the Design of Selective Inhibitors," Trends in Pharmacological Sciences, 11, 150-155 (1990).
Sambrook et al., "Oligonucleotide-Mediated Mutagenesis," Ch. 15 in Molecular Cloning: A Laboratory Manual, 2nd Ed., Cold Spring Harbor Press, Long Island, N.Y., 1989, pp. 15.51-1580.
Anderson et al., "Demonstration that CFTR Is a Chloride Channel by Alteration of Its Anion Selectivity," Science, 253, 202-204 (1991).
Cheng et al. (I), "Phosphorylation of the R Domain by cAMP-Dependent Protein Kinase Regulates the CFTR Chloride Channel," Cell, 66, 1027-1036 (1991).
Gregory et al.(I), "Expression and Characterization of the Cystic Fibrosis Transmembrane Conductance Regulator," Nature, 347, 382-386 (1990).
Boucher et al., "Na.sup.+ Transport in Cystic Fibrosis Respiratory Epithelia," J. Clin. Invest., 78, 1245-1252 (1986).
Cheng et al. (II), "Defective Intracellular Transport and Processing of CFTR Is the Molecular Basis of Most Cystic Fibrosis," Cell, 827-834 (1990).
Cliff et al., "Separate Cl.sup.- Conductances Activated by cAMP and Ca.sup.2+ in Cl.sup.- -Secreting Epithelial Cells," Proc. Nat. Acad. Sci. USA, 87, 4956-4960 (1990).
Frizzell, "Cystic Fibrosis: A Disease of the Ion Channels?" Trends in Neuroscience, 10(5), 190-193 (1987).
Frizzell et al., "Altered Regulation of Airway Epithelial Cell Chloride Channels in Cystic Fibrosis,".
Cheng et al.(III), "Increased Sulfation of Glycoconjugates by Cultured Nasal Epithelial Cells from Patients with Cystic Fibrosis," J. Clin. Invest., 68-72 (1989).
Gregory et al. (II), "Maturation and Function of Cystic Fibrosis Transmembrane Conductance Regulator Variants Bearing Mutations in Putative Nucleotide-Binding Domains 1 and 2," Mole. Cell. Biol., 11(8), 3886-3893 (1991).
Hyde et al., "Structural Models of ATP-Binding Proteins Associated with Cystic Fibrosis, Multidrug Resistance and Bacterial Transport," Nature, 346, 362-365 (1990).
Kartner et al., "Expression of the Cystic Fibrosis Gene in Non-Epithelial Invertebrate Cells Produces a Regulated Anion Conductance," Cell, 64, 681-691 (1991).
Knowles et al., "Activation by Extracellular Nucleotides of Chloride Ion Secretion in the Airway Epithelia of Patients with Cystic Fibrosis," N. Engl. J. Medicine, 325(8), 533-538 (1991).
Li et al., "Cystic AMP-Dependent Protein Kinase Opens Chloride Channels in Normal But Not in Cystic Fibrosis Airway Epithelial," Nature, 321, 358-360 (1988).
Quinton, "Cystic Fibrosis: A Disease in Electrolyte Transport," FASEB J., 4, 2709-2717 (1990).
Rich et al. (I), "Expression of Cystic Fibrosis Transmembrane Conductance Regulator Corrects Defective Chloride Channel Regulation in Cystic Fibrosis Airway Epithelial Cells," Nature, 347, 358-363 (1990).
Rich et al. (II), "Effect of Deleting the R Domain on CFTR-Generated Chloride Channels," Science, 253, 205-207 (1991).
Rommens et al. (II), "cAMP-Inducible Chloride Conductance in Mouse Fibroblast Lines Stably Expressing the Human Cystic Fibrosis Transmembrane Conductance Regulator," Proc. Nat. Acad. Sci. USA, 88, 7500-7504 (1991).
Sato et al., "Defective Beta Adrenergic Response of Cystic Fibrosis Sweat Glands in Vivo and In Vitro," J. Clin. Invest., 73, 1763-1771 (1984).
Schoumacher et al. (II)., "Phosphorylation Fails to Activate Chloride Channels from Cystic Fibrosis Airway Cells," Nature, 330, 752-754 (1987).
Tabcharani et al., "Phosphorylation-Regulated Cl.sup.- Channel in CHO Cells Stably Expressing the Cystic Fibrosis Gene," Nature, 352, 628-631 (1991).
Welsh, "Abnormal Regulation of Ion Channels in Cystic Fibrosis Epithelia," FASEB J., 4, 2718-2725 (1990).
Willumsen et al., "Activation of an Apical Cl.sup.- Conductance by Ca.sup.2+ Ionophores in Cystic Fibrosis Airway Epithelia," Am. J. Physiology, 256, C226-C233 (1989).
Venglarik et al., "A Simple Assay for Agonist-Regulated Cl and K Conductances in Salt-Secreting Epithelial Cells," Am. J. Physiology, 259, C358-C354 (1990).
Korman et al., "Expression of Human Class II Major Histocompatibility Complex Antigens Using Retrovirus Vectors," Proc. Nat. Acad. Sci. USA, 84, 2150-2154 (1987).
Wilson et al. (I), "Correction of DC-18-Deficient Lymphocytes by Retrovirus-Mediates Gene Transfer," Science, 248, 1413-1416 (1990).
Wilson et al. (II), "Correction of the Genet
Collins Francis S.
Dawson David C.
Drumm Mitchell L.
Wilkinson Daniel J.
Crane L. Eric
Robinson Douglas W.
The Regents of the University of Michigan
LandOfFree
Method of testing potential cystic fibrosis treating compounds u does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Method of testing potential cystic fibrosis treating compounds u, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method of testing potential cystic fibrosis treating compounds u will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2418886