Drug – bio-affecting and body treating compositions – Enzyme or coenzyme containing – Hydrolases
Reexamination Certificate
2000-09-13
2002-10-29
Hartley, Michael G. (Department: 1617)
Drug, bio-affecting and body treating compositions
Enzyme or coenzyme containing
Hydrolases
C424S001410, C424S001490, C435S007100, C435S173300
Reexamination Certificate
active
06471960
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to an improved method for preventing or treating vascular hemorrhaging. More specifically, the invention concerns methods for providing improved thrombolytic therapy to individuals who receive such therapy, and for diagnosing and treating diseases, such as Alzheimer's Disease, that are characterized by the deposition of amyloid deposits. The invention further relates to therapeutic agents for the prevention of the vascular and cellular damage induced by amyloid deposits. This invention was funded with Government funds (R01AG10462 and R01AG11525). The Government has certain rights in this invention.
BACKGROUND OF THE INVENTION
I. Plasminogen and Plasminogen Activators
The serum protein, plasminogen, plays an integral role in the proteolytic dissolution (or fibrinolysis) of blood clots. Plasminogen is an inactive “proenzyme.” It has a specific affinity for fibrin, and thus becomes incorporated into blood dots as they form. Plasminogen's proteolytic activity is released by “plasminogen activators” (“PA”) that specifically cleave the molecule to yield the active protease, plasmin. Plasmin is capable of digesting the fibrin threads of blood clots, as well as other substances involved in creating blood clots, such as fibrinogen, factor V, factor VIII, prothrombin, and factor XI (for review, see Danø, K. et al.,
Adv. Canc. Res
. 44:139-266 (1985), herein incorporated by reference)).
Plasmin is a serine protease, and exhibits substantial amino add and mechanistic homology with trypsin, chymotrypsin, and pancreatic elastase. Plasmin has a relatively broad trypsin-like specificity, hydrolyzing proteins and peptides at lysyl and arginyl bonds (Castellino, R. W. et al.,
Meth. Enzymol
. 80:365-380 (1981); Danø, K. et al.,
Adv. Canc. Res
. 44:139-266 (1985)).
Two classes of natural mammalian plasminogen activators have been described: urokinase-type plasminogen activator and tissue-type plasminogen activator (“t-PA”) (Danø, K. et al.,
Adv. Canc. Res
. 44:139-266 (1985); Devlin, et al., PCT appl. WO88/05081; Kasaia et al., U.S. Pat. No. 5,098,840; Hayashi, S. et al., U.S. Pat. No. 4,851,345; Sasaki et al., U.S. Pat. 4,258,030; Hayashi, S. et al., U.S. Pat. No. 5,004,609; Pyke, C. et al.,
Amer. J. Pathol
. 138:1059-1067 (1991); Madison, E. L. et al.,
Nature
339:721-724 (1989); Blasi, F. et al.,
J. Cell. Biol
. 104:801-804 (1987)). These two classes of molecules can be distinguished immunologically, by tissue localization, and by the stimulation of their activity by fibrin. In addition, a third plasminogen activator, streptokinase, has also been described. Streptokinase differs from urokinase and t-PA in that it is a bacterial protein produced by the streptococci.
Urokinase-type plasminogen activator (UK) is a multi-domain protein with one domain being a trypsin-like serine protease (Castellino, R. W. et al.,
Meth. Enzymol
. 80:365-380 (1981); Danø, K. et al.,
Adv. Canc. Res
. 44:139-266 (1985); Stra&bgr;burger, W. et al.,
FEBS Lett
. 157:219-223 (1983)). This protease domain converts plasminogen to plasmin by cleavage at an arginyl residue (Castellino, R. W. et al.,
Meth. Enzymol
. 80:365-380 (1981); Danø, K. et al.,
Adv. Canc. Res
. 44:139-266 (1985)). The amino add sequence and three-dimensional structure of several serine proteases, including trypsin, chymotrypsin, and elastase have been deduced (Danø, K. et al.,
Adv. Canc. Res
. 44:139-266 (1985); Stra&bgr;burger, W. et al.,
FEBS Lett
. 157:219-223 (1983)).
Urokinase is synthesized in the kidneys, and can be recovered from urine. It is initially produced as a single chain protein, “pro-urokinase” that can be proteolytically cleaved by plasmin into an active two-chain protein (Devlin, et al., PCT appl. WO88/05081).
Tissue-type plasminogen activator (t-PA) is produced by the cells that line the lumen. of blood vessels or endothelial cells. Like urokinase, t-PA is also initially produced as a single-chain molecule (Rijken, D. G. et al.,
J. Biol. Chem
. 256:7035-7041 (1981); Pennica, D. et al.,
Nature
301:214-221 (1983)).
The known plasminogen activators differ significantly in characteristics such as their biological half-lives and their preference for fibrin. All three classes of activators have been widely used as thrombolytic agents for the treatment of thrombosis in myocardial infarction, stroke, arterial occlusion, etc. (Kasai et al., U.S. Pat. No. 5,098,840; Hayashi et al., U.S. Pat. No. 5,004,609; Hayashi et al., U.S. Pat. No. 4,851,345; Sasaki et al., U.S. Pat. No. 4,258,030).
The administration of t-PA for the treatment of thrombosis in myocardial infarction, stroke, arterial occlusion, and other cardiovascular diseases reflects the production of minute blood clots which are formed during the disease process. The presence of such clots significantly increases the criticality of the disease, and increases its morbidity. Since t-PA is able to activate plasminogen to plasmin, it is capable of initiating the cascade of events needed to dissolve undesired blood clots. As such, its administration significantly decreases the mortality associated with myocardial infarction and other acute cardiovascular conditions.
Unfortunately, the use of t-PA and streptokinase has been associated with the occurrence of hemorrhages in some individuals (Pendlebury, W. W. et al.,
Annls. Neurol
. 28:210-213 (1989); Wijdicks, E. F. M. et al.,
Stroke
24:554-557 (1993); Kase, C. S. et al.,
Annls. Intern. Med
. 112:17-21 (1990); Molinari, G. F.
Stroke
24:523-526 (1993);), particularly when administered with anti-clotting factors such as coumarin or heparin. This phenomenon has limited the use of t-PA and streptokinase to treat cardiovascular disease in certain classes of patients, notably, the elderly (Topol, E. J. et al.,
New Engl. J. Med
. 327:45-47 (1992); De Jaegere, P. P. et al.,
J. Amer. Col. Cardiol
. 19:289-294(1992); Gore, J. M. et al.,
Circulation
183:448-459 (1991)).
II. Alzheimer's Disease and Related Conditions
Alzheimer's Disease (“AD”) is a progressive disease of the human central nervous system. It is manifested by dementia in the elderly, by disorientation, loss of memory, difficult with language, calculation, or visual-spatial skills, and by psychiatric manifestations. It is associated with degenerating neurons in several regions of the brain. Alzheimer's Disease is reviewed by Price, D. L. et al. (
Clin. Neuropharm
. 14:S9-S14 (1991)); Pollwein, P. et al. (
Nucl. Acids Res
. 20:63-68 (1992)); Regland, B. et al. (
Med. Hypoth
. 38:11-19 (1992)) and Johnson, S. A. (In: Review of Biological Research in Aging, Vol. 4., Rothstein, M. (Ed.), Wiley-Liss, NY, 163-170 (1990)).
Pathologically, Alzheimer's Disease is recognized by the presence of intracellular tangles, and an extracelluar 39-43 amino add peptide known as the &bgr;/A4amyloid peptide (Price, D. L. et al.,
Clin. Neuropharm
. 14:S9-S14 (1991); Podlisny, M. B. et al.,
Science
238:669-671 (1987); Currie, J. R. et al.,
J. Neurosci. Res
. 30:687-689 (1991)). The fibrils formed by this peptide are concentrated in amyloid deposits in the extracellular space of the brain parenchyma and in the vascular elements of the brain and the pia-arachnoid (Currie, J. R. et al.,
J. Neurosci. Res
. 30:687-689 (1991)). All cases of Alzheimer's Disease show such deposition of amyloid in brain parenchyma.
The amyloid peptide is produced from the proteolytic cleavage of an amyloid precursor protein (“APP”) which is encoded by the APP gene located on chromosome 21. The APP gene is preferentially expressed in the brain cells of the central nervous system. APP mRNA is processed by alternate splicing, and by proteolytic cleavage, such that different isoforms of APP are generated (Pollwein, P. et al. (
Nucl. Acids Res
. 20:63-68 (1992); Price, D. L. et ad.,
Clin. Neuropharm
. 14:S9-S14 (1991)).
Researchers have proposed that APP is a cell surface receptor or a transmembrane protein, in which the &bgr;/A4 domain is partly embedded in the cell membrane. The secretion of the &bgr;/A4 peptide thus reflects the
Hartley Michael G.
Licata & Tyrrell P.C.
Rutgers, the State University
Willis Michael A.
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