Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Bacterium or component thereof or substance produced by said...
Reexamination Certificate
2001-05-29
2003-10-14
Low, Christopher S. F. (Department: 1653)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Bacterium or component thereof or substance produced by said...
C424S236100, C424S282100, C424S434000, C424S810000, C514S002600, C514S012200, C514S014800, C530S350000, C435S007100, C435S006120, C435S069100, C435S325000, C435S368000, C435S371000
Reexamination Certificate
active
06632440
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to treatment of mucus hypersecretion, to compositions therefor and manufacture of those compositions. The present invention relates particularly, though not exclusively, to the treatment of chronic bronchitis in chronic obstructive pulmonary disease (COPD), asthma and other clinical conditions involving COPD.
BACKGROUND OF THE INVENTION
Mucus is a thin film of protective viscoelastic liquid which lines the airways. It is a 1-2% aqueous solution, in which the major components are the glycoconjugates known as mucins. Mucus, including the mucins, is secreted by mucus secretory cells, the surface epithelial goblet cells of the large airways and the mucus cells of the submucosal glands. Mucin release occurs by three mechanisms: constitutive secretion, regulated secretion and protease cell surface activity. Of these it is regulated secretion that responds to external stimuli and is amenable to therapeutic intervention in COPD and asthma. Regulated secretion involves release from intracellular granules by docking and fusion of the granules with the cell exterior to release their contents onto the airway surface. Fusion of the granules can either be with the plasma membrane of the epithelial cell or with the membrane of other granules leading to release via multigranular complexes fused at the cell surface. Regulated secretion of mucins is controlled by humoral factors and by neural mechanisms. The neural mechanisms in humans involve a minor contribution from the adrenergic, sympathetic pathway and a major cholinergic, parasympathetic component. Another important neural pathway regulating mucin secretion, particularly the hypersecretion of pathological conditions, is that of the Non-Adrenergic Non-Cholinergic (NANC) pathway. The NANC component involves both an orthodromic pathway involving neuropeptide and nonpeptide transmitters, and a local sensory efferent pathway involving antidromic fibres from sensory C fibres.
COPD is a common respiratory condition, being the fourth most common cause of death in middle age in the Western world. COPD comprises two related diseases, which usually occur together, emphysema and chronic bronchitis. The pathological basis of chronic bronchitis is mucus hypersecretion. The excessive, chronic bronchial secretion results in expectoration, and can last from a few days to many years. The mucus hypersecretion of COPD results in small airway obstruction producing reduced maximal respiratory flow and slow forced lung emptying. There is minimal reversal of the impaired airway function of COPD by bronchodilators and currently no effective therapy for the mucus hypersecretion.
Mucus hypersecretion is also a significant contributing factor to the pathophysiology of asthma. It is a key component in
status asthmaticus
, and contributes to the chronic symptoms and morbidity of asthma. The mucus hypersecretion component of asthma is not well controlled by current therapies, particularly in severe and chronic cases.
It would accordingly be desirable to treat, reduce or prevent the mucus hypersecretion that causes or leads to these disease conditions.
SUMMARY OF THE INVENTION
Accordingly, the invention provides a method of treating mucus hypersecretion comprising inhibiting mucus secretion by mucus secreting cells and/or inhibiting neurotransmitter release from neuronal cells that control or direct mucus secretion. The invention further provides, in a second aspect, a compound, for use in the treatment of mucus hypersecretion, which inhibits mucus secretion by (i) inhibiting mucus secretion by mucus secreting cells, or (ii) inhibiting neurotransmitter release from neuronal cells controlling or directing mucus secretion.
An advantage of the invention is that an agent for effective treatment of mucus hypersecretion and associated disease states is now provided and used, offering a relief to sufferers where hitherto there was no such agent available.
The present invention thus represents a new different approach to treatment of mucus hypersecretion by inhibiting secretory processes, namely one or other or both of the mucus secretion by mucus secretory cells and the secretion of neurotransmitters regulating mucus secretion. Agents of the present invention reduce mucus secretion and/or prevent the hypersecretion of COPD and asthma, and any other disease in which mucus hypersecretion is a causative element.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
A compound of the invention typically inhibits exocytosis in mucus secreting cells or neurones that control or direct mucus secretion. This compound is administered to a patient suffering from mucus hypersecretion and inhibition of exocytosis in the cells specified results in reduction of secretion of mucus. Specific disease states caused by or exacerbated by hypersecretion are localised to the airways, and hence an embodiment of the invention comprises topical administration to the airways or to a selected region or to a selected portion of the airways of a compound that inhibits exocytosis in mucus secreting cells or in neurones that control or direct mucus secretion.
A compound of embodiments of the invention is a polypeptide that consists of or comprises an inhibiting domain which inhibits exocytosis in the mucus secreting cell or inhibits exocytosis in a neuronal cell, thereby directly inhibiting exocytosis of mucus or one or more mucus components or indirectly inhibiting mucus secretion by inhibiting exocytosis of neurotransmitter which would in turn lead to or otherwise stimulate mucus secretion. The inhibiting domain can suitably comprise a light chain of a clostridial neurotoxin, or a fragment or variant thereof which inhibits exocytosis.
The compound preferably further comprises a translocating domain that translocates the inhibiting domain into the cell. This domain may comprise a H
N
region of a botulinum polypeptide, or a fragment or variant thereof that translocates the inhibiting domain into the cell.
The compound preferably comprises a targeting domain which binds to (i) a mucus secreting cell, or (ii) a neuronal cell controlling or directing mucus secretion. The compound is thus rendered specific for these cell types. It is also optional for the compound to be relatively non-specific but for inhibition of mucus secretion to be achieved via targeting of the compound through choice of route of administration—the compound is hence preferably administered to mucus secreting epithelial cells in the airways, specifically in the lungs. Whilst a non-specific compound of the invention may affect exocytosis in many cells of a wide range of types, generally only those cells that are stimulated will be affected and these stimulated cells will in typical disease states be those that are secreting mucus and contributing to disease.
When present, suitable targeting domains include, but are not restricted to, a domain selected from Substance P, VIP, beta
2
adrenoreceptor agonists, gastrin releasing peptide and calcitonin gene related peptide. The precise cells targeted in preferred embodiments of the invention are selected from (a) cells that secrete mucins, such as epithelial goblet cells and submucosal gland mucus secreting cells, (b) cells that secrete aqueous components of mucus, such as Clara cells and serous cells, and (c) cells that control or direct mucus secretion, such as “sensory-efferent” C-fibres, or NANC neural system fibres. The compound may be administered as a substantially pure preparation all targeted to the same cell type, or may be a mixture of compounds targeted respectively to different cells.
The compound of specific embodiments of the invention comprises first, second and third domains. The first domain is adapted to cleave one or more vesicle or plasma-membrane associated proteins essential to exocytosis. This domain prevents exocytosis once delivered to a targeted cell. The second domain translocates the compound into the cell. This domain delivers the first domain into the cell. The third domain binds to the target cell, ie binds to (i) a mucus s
Chaddock John Andrew
Foster Keith Alan
Quinn Conrad Padraig
Health Protection Agency
Kam Chih-Min
Low Christopher S. F.
Sterne Kessler Goldstein & Fox P.L.L.C.
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