Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues
Reexamination Certificate
1995-10-20
2001-06-19
Pak, Michael (Department: 1646)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
C536S023400, C435S069700
Reexamination Certificate
active
06248867
ABSTRACT:
FIELD OF THE INVENTION
The present invention is in the fields of diagnostics, and concerns methods and reagents for diagnosing glaucoma and related disorders. This invention was supported with Government funds (NIH EY02477 and NIH EY 08905-02). The Government has certain rights in this invention.
BACKGROUND OF THE INVENTION
“Glaucomas” are a group of debilitating eye diseases that are the leading cause of preventable blindness in the United States and other developed nations. Primary Open Angle Glaucoma (“POAG”) is the most common form of glaucoma. The disease is characterized by the degeneration of the trabecular meshwork, leading to obstruction of the normal ability of aqueous humor to leave the eye without closure of the space (e.g., the “angle”) between the iris and cornea (see, Vaughan, D. et al., In:
General Ophthamology
, Appleton & Lange, Norwalk, Conn., pp. 213-230 (1992)). A characteristic of such obstruction in this disease is an increased intraocular pressure (“IOP”), resulting in progressive visual loss and blindness if not treated appropriately and in a timely fashion.
The disease is estimated to affect between 0.4% and 3.3% of all adults over 40 years old (Leske, M. C. et al.,
Amer. J. Epidemiol.
113:1843-1846 (1986); Bengtsson, B.,
Br. J. Ophthamol.
73:483-487 (1989); Strong, N. P.,
Ophthal. Physiol. Opt.
13:3-7(1992)). Moreover, the prevalence of the disease rises with age to over 6% of those 75 years or older (Strong, N. P.,
Ophthal. Physiol. Opt.
12:3-7 (1992)).
A link between the IOP response of patients to glucocorticoids and the disease of POAG has long been suspected. While only 5% of the normal population shows a high IOP increase (16 mm Hg) to topical glucocorticoid testing, over 90% of patients with POAG show this response. In addition, an open angle glaucoma may be induced by exposure to glucocorticoids. This observation has suggested that an increased or abnormal glucocorticoid response in trabecular cells may be involved in POAG (Zhan, G. L. et al.,
Exper. Eye Res.
54:211-218 (1992); Yun, A. J. et al.,
Invest. Ophthamol. Vis. Sci.
30:2012-2022 (1989); Clark, A. F.,
Exper. Eye Res.
55:265 (1992); Klemetti, A.,
Acta Ophthamol.
68:29-33 (1990); Knepper, P. A., U.S. Pat. No. 4,617,299).
The ability of glucocorticoids to induce a glaucoma-like condition has led to efforts to identify genes or gene products that would be induced by the cells of the trabecular meshwork in response to glucocorticoids (Polansky, J. R. et al., In:
Glaucoma Update IV,
Springer-Verlag, Berlin, pp. 20-29 (1991)). Initial efforts using short-term exposure to dexamethasone revealed only changes in specific protein synthesis. Extended exposure to relatively high levels of dexamethasone was, however, found to induce the expression of related 66 kD and 55 kD proteins that could be visualized by gel electrophoresis (Polansky, J. R. et al., In:
Glaucoma Update IV,
Springer-Verlag, Berlin, pp.20-29 (1991)). The induction kinetics of these proteins as well as their dose response characteristics were similar to the kinetics those that were required for steroid-induced IOP elevation in human subjects (Polansky, J. R. et al., In:
Glaucoma Update IV,
Springer-Verlag, Berlin, pp. 20-29 (1991)). Problems of aggregation and apparent instability or loss of protein in the purification process were obstacles in obtaining a direct protein sequence.
Because increased IOP is a readily measurable characteristic of glaucoma, the diagnosis of the disease is largely screened for by measuring intraocular pressure (tonometry) (Strong, N. P.,
Ophthal. Physiol. Opt.
12:3-7 (1992 ), Greve, M. et al.,
Can. J. Ophthamol.
28:201-206 (1993)). Unfortunately, because glaucomatous and normal pressure ranges overlap, such methods are of limited value unless multiple readings are obtained (Hitchings, R. A.,
Br. J. Ophthamol.
77:326 (1993); Tuck, M. W. et al.,
Ophthal. Physiol. Opt.
13:227-232 (1993); Vaughan, D. et al., In:
General Ophthamology,
Appleton & Lange, Norwalk, Conn., pp. 213-230 (1992); Vernon, S. A.,
Eye
7:134-137 (1993)). For this reason, additional methods, such as direct examination of the optic disk and determination of the extent of a patient's visual field loss are often conducted to improve the accuracy of diagnosis (Greve, M. et al.,
Can. J. Ophthamol.
28:201-206 (1993)).
In view of the importance of glaucoma, and the at least partial inadequacies of prior methods of diagnosis, it would be desirable to have an improved, more accurate method for diagnosing glaucoma. The present invention provides such improved diagnostic agents and methods.
SUMMARY OF THE INVENTION
The invention concerns a novel peptide sequence discovered to be highly induced by glucocorticoids in the endothelial lining cells of the human trabecular meshwork. The cDNA for this protein, the protein itself, molecules that bind to it, and nucleic acid molecules that encode it, provide improved methods and reagents for diagnosing glaucoma and related disorders, as well as for diagnosing other diseases or conditions, such as cardiovascular, immunological, or other diseases or conditions that affect the expression or activity of the protein. Indeed, the molecules of the present invention may be used to diagnose diseases or conditions which are characterized by alterations in the expression of extracellular proteins. In addition, due to its cellular functions and DNA binding properties, the molecules of the present invention may be used to diagnose diseases or conditions which are characterized those functions.
The clone was termed “II.2” during the procedures of its isolation and was subsequently renamed “TIGR” (“Trabecular Meshwork Induced Glucocorticoid Response”) protein.
In detail, the invention provides a substantially purified TIGR protein having the sequence of SEQ ID NO:1 residues 1-497 or 15-197.
The invention further provides a nucleic acid molecule that encodes a TIGR protein, especially a nucleic acid molecule that comprises the sequence of SEQ ID NO:2 or SEQ ID NO:3.
The invention also provides an antibody capable of specifically binding to a TIGR protein.
The invention also provides a method for diagnosing a glaucoma in a patient which comprises determining whether the amount of a TIGR protein present in the trabecular meshwork of an eye of the patient exceeds the amount of that TIGR protein present in the trabecular meshwork of an eye of an individual who is not suffering from glaucoma, wherein the detection of an excessive amount of the TIGR protein is indicative of glaucoma.
The invention also provides a method for quantitatively or qualitatively determing the amount of a TIGR protein present in the trabecular meshwork of an eye of an individual, and determining whether that amount exceeds the amount of that TIGR protein present in the trabecular meshwork of an eye of an individual who is not suffering from glaucoma, wherein the detection of an excessive amount of the TIGR protein is indicative of glaucoma.
REFERENCES:
patent: 4617299 (1986-10-01), Knepper
patent: 4757089 (1988-07-01), Epstein
patent: 4829088 (1989-05-01), Doulakas, Jr.
patent: 5124154 (1992-06-01), Babcock et al.
patent: 5130238 (1992-07-01), Malek et al.
patent: 5169766 (1992-12-01), Schuster et al.
patent: 5192535 (1993-03-01), Davis et al.
patent: 5420120 (1995-05-01), Boltralik
patent: 5474985 (1995-12-01), Polansy et al.
patent: 5516657 (1996-05-01), Murphy et al.
patent: 5606043 (1997-02-01), Nguyen et al.
patent: 0 329 822 A2 (1989-08-01), None
patent: WO 88/10315 (1988-12-01), None
patent: WO 89/06700 (1989-07-01), None
patent: WO89/06964 (1989-08-01), None
patent: WO 90/01069 (1990-02-01), None
patent: 96/14411 (1996-05-01), None
Chen et al. Expression of trabecular meshwork inducible glucocorticoid response (TIGR) peptide in SF9 cells. Investigative Opthalmology & Visual Science. vol.34, No.4, p. 1385, May 15, 1993.*
Hopp et al. Prediction of protein antigenic determinants from amino acid sequences. Proceedings of the National Academy of Sciences, USA. vol.78, No.6, pp. 3824-3828, Jun. 1981.*
Das.
Huang Weidong
Nguyen Thai D.
Polansky Jon R.
Howrey Simon Arnold & White , LLP
Pak Michael
LandOfFree
Trabecular meshwork induced glucocorticoid response (TIGR)... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Trabecular meshwork induced glucocorticoid response (TIGR)..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Trabecular meshwork induced glucocorticoid response (TIGR)... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2480479