Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1997-09-26
2001-01-09
Schwartzman, Robert A. (Department: 1635)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091100, C536S023100, C536S024100, C536S024300, C536S024310, C536S024330
Reexamination Certificate
active
06171788
ABSTRACT:
FIELD OF THE INVENTION
The present invention is in the fields of diagnostics, prognosis, and treatment, and concerns methods and reagents for diagnosing and treating glaucoma and related disorders.
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 alteration 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 Ophthalmology,
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.
12:3-7 (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, greater than 40-50% 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 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)). Moreover, these techniques are of limited prognostic value.
Nguyen et al., U.S. patent application Ser. No. 08/649,432 filed May 17, 1996, now U.S. Pat. No. 5,789,169, the entire disclosure of which is hereby incorporated by reference as if set forth at length herein, disclosed a novel protein sequence highly induced by glucocorticoids in the endothelial lining cells of the human trabecular meshwork. Nguyen et al., U.S. patent application Ser. No. 08/649,432, now U.S. Pat. No. 5,789,169 also disclosed the cDNA sequence for that protein, the protein itself, molecules that bind to it, and nucleic acid molecules that encode it, and provided 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.
The present invention provides improved diagnostic agents, prognostic agents, therapeutic agents and methods.
SUMMARY OF THE INVENTION
An object of the invention is to provide a method for diagnosing glaucoma in a patient which comprises the steps: (A) incubating under conditions permitting nucleic acid hybridization: a marker nucleic acid molecule, said marker nucleic acid molecule comprising a nucleotide sequence of a polynucleotide that specifically hybridizes to a polynucleotide that is linked to a TIGR promoter, and a complementary nucleic acid molecule obtained from a cell or a bodily fluid of said patient, wherein nucleic acid hybridization between said marker nucleic acid molecule, and said complementary nucleic acid molecule obtained from said patient permits the detection of a polymorphism whose presence is predictive of a mutation affecting TIGR response in said patient; (B) permitting hybridization between said marker nucleic acid molecule and said complementary nucleic acid molecule obtained from said patient; and (C) detecting the presence of said polymorphism, wherein the detection of the polymorphism is diagnostic of glaucoma.
Another object of the invention is to provide a method for prognosing glaucoma in a patient which comprises the steps: (A) incubating under conditions permitting nucleic acid hybridization: a marker nucleic acid molecule, said marker nucleic acid molecule comprising a nucleotide sequence of a polynucleotide that specifically hybridizes to a polynucleotide that is linked to a TIGR promoter, and a complementary nucleic acid molecule obtained from a cell or a bodily fluid of said patient, wherein nucleic acid hybridization between said marker nucleic acid molecule, and said complementary nucleic acid molecule obtained from said patient permits the detection of a polymorphism whose presence is predictive of a mutation affecting TIGR response in said patient; (B) permitting hybridization between said marker nucleic acid molecule and said complementary nucleic acid molecule obtained from said patient; and (C) detecting the presence of said polymorphism, wherein the detection of the polymorphism is prognostic of glaucoma.
Another object of the invention is to provide marker nucleic acid molecules capable of specifically detecting TIGRmt1, TIGRmt2, TIGRmt3, TIGRmt4, TIGRmt5 and TIGRsv1.
Another object of the invention is to provide a method for diagnosing steroid sensitivity in a patient which comprises the steps: (A) incubating under conditions permitting nucleic acid hybridization: a marker nucleic acid molecule, the marker nucleic acid molecule comprising a nucleotide sequence of a polynucleotide that is linked to a TIGR promoter, and a complementary nucleic acid molecule obtained from a cell or a bodily fluid of the patient, wherein nucleic acid hybridization between the marker nucleic acid molecule, and the complementary nucleic acid molecule obtained from
Chen Hua
Chen Pu
Nguyen Thai D.
Polansky Jon R.
Howrey Simon Arnold & White , LLP
Schwartzman Robert A.
Shibuya Mark L.
The Regents of the University of California
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