Compositions and methods for cystic fibrosis therapy

Details Compositions and methods for cystic fibrosis therapy Compositions and methods for cystic fibrosis therapy

1998-10-16

2001-12-11

Geist, Gary (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S513000, C514S851000

Reexamination Certificate

active

06329422

ABSTRACT:

TECHNICAL FIELD
The present invention relates generally to the treatment of cystic fibrosis. The invention is more particularly related to compositions comprising one or more compounds such as flavones and/or isoflavones, which may be used to activate chloride transport (i.e., absorption and/or secretion) in epithelial tissues of the airways, the intestine, the pancreas and other exocrine glands, and for cystic fibrosis therapy.
BACKGROUND OF THE INVENTION
Cystic fibrosis is a lethal genetic disease afflicting approximately 30,000 individuals in the United States. Approximately 1 in 2500 Caucasians is born with the disease, making it the most common lethal, recessively inherited disease in that population.
Cystic fibrosis affects the secretory epithelia of a variety of tissues, altering the transport of water, salt and other solutes into and out of the blood stream. In particular, the ability of epithelial cells in the airways, pancreas and other tissues to transport chloride ions, and accompanying sodium and water, is severely reduced in cystic fibrosis patients, resulting in respiratory, pancreatic and intestinal ailments. The principle clinical manifestation of cystic fibrosis is the resulting respiratory disease, characterized by airway obstruction due to the presence of a thick mucus that is difficult to clear from airway surfaces. This thickened airway liquid contributes to recurrent bacterial infections and progressively impaired respiration, eventually resulting in death.
In cystic fibrosis, defective chloride transport is generally due to a mutation in a chloride channel known as the cystic fibrosis transmembrane conductance regulator (CFTR; see Riordan et al.,
Science
245:1066-73, 1989). CFTR is a linear chloride channel found in the plasma membrane of certain epithelial cells, where it regulates the flow of chloride ions in response to phosphorylation by a cyclic AMP-dependent kinase. Many mutations of CFTR have been reported, the most common of which is a deletion of phenylalanine at position 508 (&Dgr;F508-CFTR), which is present in approximately 70% of patients with cystic fibrosis. A glycine to aspartate substitution at position 551 (G551D-CFTR) occurs in approximately 1% of cystic fibrosis patients.
Current treatments for cystic fibrosis generally focus on controlling infection through antibiotic therapy and promoting mucus clearance by use of postural drainage and chest percussion. However, even with such treatments, frequent hospitalization is often required as the disease progresses. New therapies designed to increase chloride ion conductance in airway epithelial cells have been proposed, but their long term beneficial effects have not been established and such therapies are not presently available to patients.
Accordingly, improvements are needed in the treatment of cystic fibrosis. The present invention fulfills this need and further provides other related advantages.
SUMMARY OF THE INVENTION
Briefly stated, the present invention provides compositions and methods for enhancing chloride transport in epithelial cells and for the therapy of cystic fibrosis. Within one aspect, the present invention provides methods for enhancing chloride transport in epithelial cells, comprising contacting epithelial cells with a compound selected from the group consisting of flavones and isoflavones, wherein the compound is capable of stimulating chloride transport and wherein the compound is not genistein. Within certain embodiments, the compound is (a) a polyphenolic compound having the general formula:
wherein carbon atoms at positions 2, 3, 5, 6, 7, 8, 2′, 3′, 4′, 5′ and 6′ are bonded to a moiety independently selected from the group consisting of hydrogen atoms, hydroxyl groups and methoxyl groups, and wherein X is a single bond or a double bond; or (b) a stereoisomer or glycoside derivative of any of the foregoing polyphenolic compounds. Such compounds include, within certain embodiments, quercetin, apigenin, kaempferol, biochanin A, flavanone, flavone, dihydroxyflavone, trimethoxy-apigenin, apigenin 7-O-neohesperidoside, fisetin, rutin, daidzein and prunetin. For enhancing chloride transport in airway epithelial cells of a mammal, compounds may be administered orally or by inhalation. Other epithelial cells that may be employed include intestinal, pancreas, gallbladder, sweat duct, salivary gland and mammary epithelial cells. Within certain embodiments, the compound is combined with a substance that increases expression of a CFTR; and/or a chemical chaperone that increases trafficking of a CFTR to the plasma membrane.
Within other aspects, methods for enhancing chloride transport in epithelial cells may comprise contacting epithelial cells with a compound selected from the group consisting of reservatrol, ascorbic acid, ascorbate salts and dehydroascorbic acid. Such compounds may further be used in combination with a flavone or isoflavone as provided above.
Within other aspects, the present invention provides methods for treating cystic fibrosis in a patient, comprising administering to a patient a compound as described above, wherein the compound is capable of stimulating chloride transport. Within certain embodiments, the compound is genistein, quercetin, apigenin, kaempferol, biochanin A, flavanone, flavone, dihydroxyflavone, trimethoxy-apigenin, apigenin 7-O-neohesperidoside, fisetin, rutin, daidzein or prunetin. Within other embodiments, the compound is reservatrol, ascorbic acid, ascorbate salts and dehydroascorbic acid. Such compounds may be administered alone or in combination. Compounds may be administered orally or by inhalation. Within certain embodiments, the compound is combined with a substance that increases expression of a CFTR; and/or a chemical chaperone that increases trafficking of a CFTR to the plasma membrane.
Within further related aspects, the present invention provides methods for increasing chloride ion conductance in airway epithelial cells of a patient afflicted with cystic fibrosis, wherein the patient's CFTR protein has a deletion at position 508, the method comprising administering to a mammal one or more compounds as described above, wherein the compound is capable of stimulating chloride secretion in the airway epithelial cells.
Within still further related aspects, the present invention provides methods for increasing chloride ion conductance in airway epithelial cells of a patient afflicted with cystic fibrosis, wherein the patient's CFTR protein has a mutation at position 551, the method comprising administering to a mammal one or more compounds as described above, wherein the compound is capable of stimulating chloride secretion in the airway epithelial cells.
Within further aspects, pharmaceutical compositions for treatment of cystic fibrosis are provided, comprising (a) one or more flavones or isoflavones capable of stimulating chloride transport and (b) one or more of: (i) a compound that increases expression of a CFTR in an epithelial cell; and/or (ii) a chemical chaperone that increases trafficking of a CFTR to a plasma membrane in an epithelial cell; and; and in combination with a pharmaceutically acceptable carrier. Within certain embodiments, the flavone or isoflavone may be genistein, quercetin, apigenin, kaempferol, biochanin A, flavanone, flavone, dihydroxyflavone, trimethoxy-apigenin, apigenin 7-O-neohesperidoside, fisetin, rutin, daidzein and/or prunetin, in combination with a pharmaceutically acceptable carrier.
Within still further aspects, a pharmaceutical composition for treatment of cystic fibrosis may comprise: (a) a polyphenolic compound having the general formula:
wherein carbon atoms at positions 2, 3, 5, 6, 7, 8, 2′, 3′, 4′, 5′ and 6′ are bonded to a moiety independently selected from the group consisting of hydrogen atoms, hydroxyl groups and methoxyl groups, and wherein X is a single bond or a double bond; or a stereoisomer or glycoside derivative of any of the foregoing polyphenolic compounds; (b) a compound selected from the group c

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