Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues
Patent
1992-06-16
1995-05-02
Patterson, Jr., Charles L.
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
530395, C07K 1300, A61K 3764
Patent
active
054120730
DESCRIPTION:
BRIEF SUMMARY
This invention relates to polypeptides, especially polypeptides having activity of the serine-protease inhibitor type, to DNA encoding therefor and to pharmaceutical preparations containing the inhibitor.
Proteolytic enzymes released during the inflammatory process, by neutrophils in particular, are thought to play a central role in tissue damage associated with chronic lung diseases such as pulmonary emphysema and bronchiectasis (Janoff A (1985) Am Rev Resp Dis 132, 417). Most individuals remain relatively healthy with minimal tissue damage following an inflammatory response because the blood and lung tissues contain several inhibitors to counteract the effects of proteinases (Stockley R (1983) Clin Sci 64, 119).
.alpha..sub.1 -antitrypsin (AAT) is a major inhibitor of serine proteinases present in the blood and in lung secretions. Its major physiological function is to protect the lower respiratory tract from neutrophil elastase, an enzyme implicated in the damage of lung connective tissue that occurs in chronic lung disease (Carell RW, Jeppsson JO, Laurell CB et al. (1982) Nature 298, 329).
Individuals with inherited deficiency of AAT are predisposed to developing early onset adult pulmonary emphysema particularly if they smoke (Laurell CB, Eriksson S. (1963) Scand J Clin Lab Invest 15, 132). Although other serine proteinase-inhibitors probably also play a role in protecting the lung from proteolytic degradation, these have either been poorly characterised or genetic abnormalities of these inhibitors have yet to be described in association with chronic lung disease. It seems likely that other genetic factors contribute to chronic lung disease. Of potential relevance are abnormalities in related proteins. Previous reports suggested that there may be immunologically cross-reacting material detected by antibodies to .alpha..sub.1 -antitrypsin (Glew RH, Zidian JL, Chiao JP et al (1981) In: "Electrophoresis" Walter de Gruyter, page 5115; Mittman C, Teevee B, Lieberman J (1973) J Occ Med 15, 33) and three related genes have been detected in a rat liver cDNA library (Krauter KS, Citron BA, Hsu MT (1986) DNA 5, 29) suggesting that other putative serine proteinase-inhibitors remain to be characterised.
Less than 5% of all patients who develop pulmonary emphysema have a clearly identifiable abnormality of AAT protein (Mittman C, Teevee B, Lieberman J (1973) J Occ Med 5, 33) and only about 10-20% of cigarette smokers are particularly vulnerable to the onset of pulmonary emphysema (Niewhoner DE (1983) In: "Textbook of Pulmonary Diseases" page 915). A polymorphism of the AAT gene that occurs in about 20% of patients with pulmonary emphysema has recently been described (Kalsheker NA, Hodgson IJ, Watkins GL et al. (1986) Am Rev Resp Dis 133, A219). This polymorphism may be linked to other candidate genes involved in the pathogenesis of chronic lung disease. It is now known that in humans two other potentially important genes occur within 100 kilobase pairs (kb) to AAT on chromosome 14. These are .alpha..sub.1 -antichymotrypsin (ACT) (Rabin M, Watson M, Kidd Vet al. (1986) Somat Cel Mol Genet 12, 209) and an AAT gene-related sequence (ASRG) (Lai E, Kao F, Law Met al. (1983) Am J Hum Genet 35, 385) which may code for a serine proteinase-inhibitor with an anti-elastase activity (according to Professor S. Woo, Baylor Medical School, Houston, Tex.).
The isolation of several AAT cDNA clones from a human liver cDNA library has previously been reported (Kalsheker N, Chiswell D, Markham A et al (1985) Ann Clin Biochem 2225).
Although an understanding of the structure and role of AAT is clearly of major significance in the diagnosis and potential management of pulmonary emphysema, it is clear that AAT is unlikely to provide a complete answer. A problem facing workers in the field is to identify further serine protease inhibitors, not least so that they can be studied to develop further understanding of disease such as pulmonary emphysema.
Nucleic acid having significant nucleotide sequence differences from DNA coding for AAT an
REFERENCES:
Clarke-Lewis et al 1986. Science 231:134-139.
Long et al. 1984 Biochemistry 23:4828-4837.
Chem. Abstracts 100 (1984) :405 #155002j.
3i Research Exploitation Limited
Irons Edward S.
Patterson Jr. Charles L.
LandOfFree
Polypeptides and DNA coding therefor does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Polypeptides and DNA coding therefor, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Polypeptides and DNA coding therefor will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1138123