Methods for treating blood coagulation disorders

Abstract

The present invention relates to a method of treating an individual having a blood coagulation defect (e.g., hemophilia A, hemophilia B), comprising administering to the individual an effective amount of a DNA vector encoding modified Factor VII (FVII), wherein the modified Factor VII leads to generation of Factor VIIa in vivo. In a particular embodiment, the invention pertains to a method of treating an individual having a blood coagulation defect comprising administering to the individual an effective amount of a nucleic acid encoding a modified FVII wherein the modified FVII comprises a signal which codes for precursor cleavage by furin at the activation cleavage site of the modified FVII. The invention also relates to a method of treating an individual having a blood coagulation disorder comprising administering to the individual an effective amount of a nucleic acid encoding the light chain of human FVII and a nucleic acid encoding the heavy chain of human FVII operably linked to a leader sequence. Compositions, expression vectors and host cells comprising nucleic acid which encodes a modified Factor VII, wherein the modified Factor VII leads to generation of Factor VIIa in vivo is also encompassed by the present invention.

Description

[0001]This application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Application Ser. Nos. 60 / 243,046 filed Oct. 25, 2000 and 60 / 307,492 filed Jul. 24, 2001 respectively. The contents of these applications are hereby incorporated by reference into the present disclosure.BACKGROUND OF THE INVENTION[0002]Hemophilia is an X-linked bleeding disorder that results from a deficiency in coagulation factor VIII (hemophilia A) or factor IX (hemophilia B). Patients are conventionally treated by protein replacement therapies using plasma-derived or recombinant factor VIII or factor IX. Gene therapies for both hemophilia A and B are in various stages of pre-clinical and clinical trails. However, 25% of hemophilia A patients develop inhibitors (e.g., antibodies) to factor VIII and about 5% of hemophilia B patients generate inhibitors to factor IX. These inhibitors lead to the ineffectiveness of protein replacement or gene replacement therapies.[0003]It is known that b...

AI Technical Summary

Benefits of technology

The present invention provides methods for treating blood coagulation defects, such as hemophilia, by administering a DNA vector expressing modified Factor VII. The modified Factor VII can be cleaved by furin to form activated Factor VII, which can then form disulfide bonds to form activated Factor VII. The DNA vector can be delivered using viral or non-viral vectors, such as plasmid DNA or liposomes. The invention also includes methods for treating individuals with inhibitors to Factor VIII or Factor IX using the modified Factor VII. The invention further includes compositions and expression vectors containing the modified Factor VII. The technical effects of the invention include improved treatment for blood coagulation defects and the ability to target specific cells using DNA vectors.

Problems solved by technology

These inhibitors lead to the ineffectiveness of protein replacement or gene replacement therapies.

In the absence of activated FVIIa, the intrinsic blood clotting pathway involving FVIII and FIX, is severely limited in effective coagulation.

However, recombinant FVIIa is expensive to manufacture.

Anther critical problem is the short half life (2 hours) of recombinant FVIIa.

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