Drug – bio-affecting and body treating compositions – Enzyme or coenzyme containing – Hydrolases
Reexamination Certificate
1998-04-10
2001-03-13
Tate, Christopher (Department: 1651)
Drug, bio-affecting and body treating compositions
Enzyme or coenzyme containing
Hydrolases
C424S094100, C424S094600, C514S851000
Reexamination Certificate
active
06200564
ABSTRACT:
BACKGROUND OF THE INVENTION
Cystic fibrosis (CF) is a common lethal genetic disorder affecting approximately 1 in 2000 Caucasians
1
. The major pathological manifestations in CF are obstruction of pulmonary, gastrointestinal and pancreatobiliary ducts by accumulation of mucoid secretions ultimately leading to organ failure, particularly in the lung. The basic cellular defect in CF is abnormal chloride transport due to mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene
2-7
. The CFTR gene encodes a protein required for the normal function of a cAMP regulated chloride channel present in secretory and other cells throughout the body. Despite rapid advances in our knowledge of the structure and function of CFTR, the cellular and physiological basis of the mucus abnormalities in CF remain obscure.
Liver disease is the second leading cause of death in CF, after lung disease
8,9
. The major hepatic manifestation of CF is a distinct form of focal biliary cirrhosis, a condition that may be accompanied or preceded by inspissated cosinophilic material resembling the mucoid material found in other organs of CF patients
10
. Approximately 20% of surviving adolescents and adults with CF have morphologic evidence of liver disease, and about 10 to 15% of these develop complications of fibrosis, cirrhosis and portal hypertension requiring transplantation
11
. Other manifestations of biliary tract disease in CF include biliary sludge and casts, increased incidence of gallstones and common bile duct strictures. Very little is known of the pathogenesis of hepatobiliary disease in CF, and detailed analysis of the inspissated material plugging bile ductules has not been published. The abnormalities in biliary secretion are assumed to be related to the known single gene defect in CF, mutation of the CFTR. Recent studies by Cohen et al
12
have documented that CFTR is localized in liver exclusively to the apical membrane of bile duct cells, but not in hepatocytes. This suggests that the hepatobiliary abnormalities in CF, particularly focal biliary cirrhosis, originate in bile duct cells, possibly by dysregulation of glycoprotein synthesis.
The availability of immortalized human intrahepatic biliary epithelial cells from normal and CF patients allow direct comparison of synthesis and secretion of biliary macromolecules in vitro.
SUMMARY OF THE INVENTION
This invention is based, at least in part, on the discovery that the major glucoconjugate secreted by IBE cells is chondroitin sulfate and more significantly that the secretion of this proteoglycan is dysregulated in CF-IBE cells compared to cells with normally functioning CFTR.
The present invention pertains to methods for treating subjects having disorders characterized by the obstruction of pulmonary, gastrointestinal and pancreatobiliary ducts by the accumulation of mucoid secretions. For example, the invention pertains to methods for treating a subject having a disorder characterized by the obstruction of organ ducts by the accumulation of mucoid secretions, e.g., a pulmonary disorder, e.g., lung failure occurring in patients afflicted with, e.g., cystic fibrosis. These methods include administering to the subject an agent capable of preventing chondroitin sulfate accumulation such that treatment of the subject occurs.
In a preferred embodiment, the agent is capable of preventing chondroitin sulfate accumulation by degrading chondroitin sulfate. In another preferred embodiment, the agent is capable of preventing chondroitin sulfate accumulation by inhibiting the production of chondroitin sulfate.
In another embodiment, the invention pertains to methods for treating a subject having a pancreatobiliary disorder, e.g., biliary cirrhosis, biliary sludge, gallstones, and common bile duct strictures comprising administering to the subject an agent capable of preventing chondroitin sulfate accumulation such that treatment occurs.
In a preferred embodiment, the agent capable of preventing chondroitin sulfate accumulation is an enzyme, e.g., chondroitinase enzyme. In still another embodiment, the agent capable of degrading chondroitin sulfate, e.g., an enzyme, e.g., chondroitinase enzyme, is produced in recombinant expression vector and host cell for use in gene therapy for treating a subject.
The invention also pertains to methods for detecting or diagnosing a disorder characterized by the obstruction of pulmonary, or pancreatobiliary ducts by the accumulation of mucoid secretions, e.g., cystic fibrosis. In one embodiment, the method involves contacting a cell, tissue, or fluid sample, e.g., a sputum sample, from the subject with an agent, e.g.
3
H-glucosamine, capable of detecting a glycosaminoglycan (GAG), e.g., chondroitin sulfate, determining the amount of chondroitin sulfate expressed in the sample, comparing the amount of chondroitin sulfate expressed in the sample to a control sample and forming a diagnosis based on the amount of chondroitin sulfate expressed in the sample as compared to the control sample. Kits for detecting chondroitin sulfate in a biological sample are also within the scope of the invention.
The invention also pertains to methods for monitoring a previously diagnosed subject with a disease characterized by the obstruction of pulmonary or pancreatobiliary ducts by the accumulation of mucoid secretions, e.g., pulmonary, gastrointestinal, or pancreatobiliary disorders, e.g., lung failure, biliary cirrhosis, biliary sludge, gallstones, or common bile strictures in a biological sample. These methods involve contacting a cell, tissue, or fluid sample, e.g., a sputum sample, from the subject with an agent, e.g.,
3
H-glucosamine, capable of detecting a glycosaminoglycan (GAG), e.g., chondroitin sulfate, determining the amount of chondroitin sulfate expressed in the sample, comparing the amount of chondroitin sulfate expressed in the sample to a the amount of chondroitin sulfate expressed in a sample previously obtained from the same subject to determine the progression of the disease, e.g., measuring the increase or decrease in levels of a GAG, e.g., chondroitin sulfate over time in a subject.
Still another aspect of the invention pertains to methods, e.g., screening assays, for identifying a compound for treating a disorder characterized by the obstruction of pulmonary, gastrointestinal and pancreatobiliary ducts by the accumulation of mucoid secretions, e.g., cystic fibrosis. These methods typically include assaying the ability of the compound or agent to prevent accumulation of a GAG, e.g., chondroitin sulfate, thereby identifying a compound for treating a disorder characterized by the obstruction of pulmonary, gastrointestinal and pancreatobiliary ducts by the accumulation of mucoid secretions, e.g., cystic fibrosis. In a preferred embodiment, the method involves contacting a biological sample obtained from a subject having the disorder with the compound or agent, determining the amount of GAG, e.g., chondroitin sulfate, expressed in the biological sample, comparing the amount of chondroitin sulfate expressed in the biological sample to that of a control sample. An alteration in the amount of chondroitin sulfate expressed in the sample exposed to the compound or agent in comparison to the control is indicative of modulating the degradation of chondroitin sulfate.
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Bataillon et al
Bhaskar K. Ramakrishnan
Green Allan M.
Lamont J. Thomas
Lahive & Cockfield LLP
Tate Christopher
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