Method of treating sickle cell disease or thalassemia

Details Method of treating sickle cell disease or thalassemia Method of treating sickle cell disease or thalassemia

1999-11-22

2002-04-16

Achutamurthy, Ponnathapu (Department: 1652)

Drug, bio-affecting and body treating compositions

Enzyme or coenzyme containing

Hydrolases

C424S094640, C435S226000, C514S002600

Reexamination Certificate

active

06372213

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to medical science particularly the treatment of sickle cell disease or thalassemia with protein C.
BACKGROUND OF THE INVENTION
Protein C is a vitamin K dependent serine protease and naturally occurring anticoagulant that plays a role in the regulation of hemostasis by inactivating Factors Va and VIIIa in the coagulation cascade. Human protein C circulates as a 2-chain zymogen, but functions at the endothelial and platelet surface following conversion to activated protein C (aPC) by limited proteolysis with thrombin in complex with the cell surface membrane protein, thrombomodulin.
In conjunction with other proteins, aPC functions as perhaps the most important down-regulator of blood coagulation resulting in protection against thrombosis. In addition to its anti-coagulation functions, aPC hasanti-inflammatory effects through its inhibition of cytokine generation (e.g. TNF and IL-1) and also exerts profibrinolytic properties that facilitate clot lysis. Thus, the protein C enzyme system represents a major physiological mechanism of anti-coagulation, anti-inflammation, and fibrinolysis.
Sickle cell diseases (SCD) and thalassemia are inherited hemoglobulinopathies characterized by a structural hemoglobin defect. SCD include diseases which cause sickling of the red blood cells, and includes sickle cell anemia (which results from rwo hemoglobulin S genes), sickle &agr;-thalassemia (one hemoglobin S and one &agr;-thalassemia gene), and hemoglobin SC disease (one hemoglobin S and one hemoglobin C), and the rarer disease, hemoglobin C Harlem. Thalassemia includes &bgr;-thalassemia and &agr;-thalassemia. These hereditary diseases have significant morbidity and mortality and affect individuals of African American heritage, as well as those of Mediterranean, Middle Eastern, and South East Asian descent. These disease commonly cause severe pain in sufferers in part due to ischemia caused by the damaged red blood cells blocking free flow through the circulatory system.
SCD is considered a prethrombotic state, since certain characteristics of sickle cells such as abnormal adhesivity and absence of membrane phospholipid asymmetry are involved in the thrombotic process [Marfaing-Koka, et al.,
Nouv Rev Fr Hamatol
35:425-430, 1993]. Most of the morbidity of SCD appears to be related to the appearance of occlusion of the microvasculature, resulting in widespread ischemia and irreversible organ damage. In addition, pulmonary microthromboemboli have been described in 44 percent of autopsies from thalassemia patients [Chuansumrit et al.,
J Med Assoc Thai,
76(2):80-84, 1993].
Investigators employing sensitive assays for coagulation have documented signs of a hypercoagulable state resulting in vaso-occlusion in adults with SCD. Vaso-occlusion is a complex process involving cellular, vascular, and humoral factors and possibly thrombotic events. The occurrence of stroke is probably the most devastating complication of SCD in a child [Peters, et al.,
Thrombosis and Haemostasis
71(2): 69-172, 1994; Tam D.,
Journal of Child Neurology
12(1):19-21, 1997].
Deficiencies of protein C and enhanced thrombin generation have been reported in patients with SCD or thalassemia [Karayalcin, et al.,
The American Journal of Pediatric Hematology/Oncology
11(3):320-323, 1989; Hazmi, et al.,
Acta Haematol
90:114-119, 1993; Peters, 1994]; Shirahata et al.
Southeast Asian J Trop Med Pub Health
23(2):65-73] The lower protein C levels in SCD or thalassemia are either due to decreased production or increased consumption. Therefore, a coagulation imbalance exists in patients with SCD or thalassemia which in turn may be responsible for the adverse clinical effects observed in these patients.
Currently, there is no effective therapy to prevent the pain associated with SCD or thalassemia or to correct the disease causing genes. The current treatment approach includes intravenous solutions of glucose and electrolytes, narcotic analgesics, and antiinflammatory agents [Green et al.
American journal of Hematology
23:317-321, 1986]. Recently, the chemotherapeutic agent hydroxyurea has been used in an increasing number of sickle cell anemia patients. In more severe cases or following ischemic stroke, exchange transfusions and bone marrow transplantation have been utilized [Ferrera et al.
American Journal of Emergency Medicine
15(7):671-679, 1997]. Prophylactic transfusion is the only accepted therapy for patients with SCD that have had a stroke. Therefore, a need exists for a safe, effective therapy of patients with SCD or thalassemia.
The present invention is the first to describe the treatment of SCD or thalassemia with protein C. Protein C, with its anticoagulant, antiinflammatory, and profibrinolytic activities, is useful for the treatment of the hypercoagulable state or protein C deficiency that occurs in SCD or thalassemic patients.
SUMMARY OF THE INVENTION
The present invention provides a method of treating a patient suffering from sickle cell disease (SCD) or thalassemia which comprises, administering to said patient a pharmaceutically effective amount of protein C.
The present invention further provides a method of treating sickle cell disease or thalassemia in a patient in need thereof, which comprises administering to said patient a pharmaceutically effective amount of activated protein C such that an activated protein C plasma level of about 2 ng/ml to about 300 ng/ml is achieved.
DETAILED DESCRIPTION OF THE INVENTION
For purposes of the present invention, as disclosed and claimed herein, the following terms are as defined below.
Protein C refers to a vitamin K dependent serine protease with anticoagulant, anti-inflammatory, and profibrinolytic properties which includes, but is not limited to, plasma derived and recombinant produced protein C. Protein C includes and is preferably human protein C although protein C may also include other species or derivatives having protein C proteolytic, amidolytic, esterolytic, and biological (anticoagulant, pro-fibrinolytic, and anti-inflammatory) activities. Examples of protein C derivatives are described by Gerlitz, et al., U.S. Pat. No. 5,453,373, and Foster, et al., U.S. Pat. No. 5,516,650, the entire teachings of which are hereby included by reference.
Zymogen—an enzymatically inactive precursor of a proteolytic enzyme. Protein C zymogen, as used herein, refers to secreted, inactive forms, whether one chain or two chains, of protein C.
Activated protein C or aPC refers to protein C zymogen which has been converted by limited proteolysis to its activated form. aPC includes and is preferably human protein C although aPC may also include other species or derivatives having protein C proteolytic, amidolytic, esterolytic, and biological (anticoagulant or pro-fibrinolytic) activities. Examples of protein C derivatives are noted above in the description of protein C.
HPC—human protein C zymogen.
r-hPC—recombinant human protein C zymogen.
r-aPC—recombinant human activated protein C produced by activating r-hPC in vitro or by direct secretion of the activated form of protein C from procaryotic cells, eukaryotic cells, and transgenic animals or plants, including, for example, secretion from human kidney 293 cells as a zymogen then purified and activated by techniques well known to the skilled artisan and demonstrated in Yan, U.S. Pat. No. 4,981,952, and Cottingham, W
0
97/20043, the entire teachings of which are herein incorporated by reference.
Plasma derived activated protein C—activated protein C produced by activating plasma HPC as described in Eibl, U.S. Pat. No. 5,478,558, the entire teaching of which is herein incorporated by reference.
Continuous infusion—continuing substantially uninterrupted the introduction of a solution into a vein for a specified period of time.
Bolus injection—the injection of a drug in a defined quantity (called a bolus) over a period of time up to about 120 minutes.
Suitable for administration—a lyophilized formulation or solution that

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