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Methods for treating blood coagulation disorders

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Title: 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. ...


Browse recent Genzyme Corporation Legal Department patents - Framingham, MA, US
Inventors: Samuel WADSWORTH, Abraham SCARIA
USPTO Applicaton #: #20110034539 - Class: 514 44 R (USPTO) - 02/10/11 - Class 514 


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The Patent Description & Claims data below is from USPTO Patent Application 20110034539, Methods for treating blood coagulation disorders.

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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

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.

It is known that basal levels of Factor VIIa in plasma are greatly reduced in patients with hemophilia B (Factor IX deficiency) and, to a lesser extent, patients with hemophilia A (Factor VIII deficiency). Wildgoose et al., Blood 1:25-28 (1992). In the absence of activated FVIIa, the intrinsic blood clotting pathway involving FVIII and FIX, is severely limited in effective coagulation. Recently, recombinant activated Factor VII (rFVIIa, NovoSeven, Novo, Nordisk) has been shown to have therapeutic value to bypass or correct the coagulation defects in hemophilia A and B patients with inhibitors, especially in patients with inhibitors who were undergoing surgical procedures. However, recombinant FVIIa is expensive to manufacture. Anther critical problem is the short half life (2 hours) of recombinant FVIIa. Therefore, recombinant FVIIa therapy requires an intravenous infusion of high doses of the protein every 2 hours.

A need exists for alternative therapies for blood coagulation disorders such as hemophilia.

SUMMARY

OF THE INVENTION

In the methods of the present invention, activated Factor VII is provided to a patient suffering from a coagulation defect, such as hemophilia. The Factor VII is delivered via DNA vectors, which may be viral or non-viral in origin. In one preferred embodiment, the activated Factor VII is provided using a DNA vector encoding a modified FVII. This modified FVII comprises a cleavage site, such as a furin cleavage site or other appropriate cleavage site, such that the modified Factor VII molecule is cleaved to form the light chain and heavy chain of Factor VII, which can then form suitable disulfide bonds to form activated Factor VII. In other preferred embodiments, activated Factor VII is supplied using DNA vectors which separately encode the light chain of Factor VII and the heavy chain of Factor VII, such that no cleavage is necessary, and the individual chains are both present and can form suitable disulfide bonds to form activated Factor VII. The individual DNA vectors which separately encode the light chain of Factor VII and the heavy chain of Factor VII may be provided on the same plasmid, either as two separate expression cassettes with separate regulatory sequences, or as part of a single polycistronic expression cassette. Alternatively, the individual DNA vectors which separately encode the light chain of Factor VII and the heavy chain of Factor VII may be provided on separate plasmids or vehicles which may be co-transformed into a single cell, so that both individual chains are present and can form suitable disulfide bonds to form activated Factor VII. In certain embodiments of the present invention, surrounding conditions, such as pH, temperature and electrovalent charges in the medium can be adjusted to optimally promote proper disulfide bonding.

The present invention further relates to 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 expressing modified Factor VII (FVII), wherein the modified Factor VII leads to generation of Factor VIIa in vivo. In one embodiment, the modified Factor VII comprises an amino acid sequence which codes for a signal for precursor cleavage by the protease furin at the activation cleavage site of the modified Factor VII. For example, the amino acid signal in the modified FVII can comprise an Arg149-X150-Lys151-Arg152 signal sequence or an Arg149-X150-Arg141-Arg152 signal sequence, such as an Arg149-Gln150-Lys151-Arg152 sequence. In another embodiment, the DNA vector encoding modified Factor VII is administered as a combination of two compositions wherein the first composition comprises the light chain (from about amino acid 1 to about amino acid 152) of human Factor VII and the second composition comprises the heavy chain from about (amino acid 153 to about amino acid 406) of human Factor VII and (operably linked to) a leader sequence (e.g., derived from a cytokine or a clotting factor). The DNA encoding modified Factor VII of the present invention can be administered as any gene transfer vector, such as viral vectors, including adenovirus, AAV, retrovirus and lentivirus, as well as plasmid DNA with or without a suitable lipid or polymer carriers, and is administered under conditions in which the nucleic acid is expressed in vivo. Alternatively, the DNA encoding modified FVII can be administered as naked DNA or in association with an amphiphilic compound, such as lipids or compounds, or with another suitable carrier.

The present invention also relates to methods of treating hemophilia in an individual, comprising administering to the individual an effective amount of a DNA vector encoding modified Factor VII wherein the modified Factor VII leads to generation of Factor VIIa in vivo. In one embodiment, the present invention relates to a method of treating hemophilia in an individual who has developed an inhibitor of Factor VIII, comprising administering to the individual an effective amount of a DNA vector encoding modified Factor VII wherein the modified Factor VII leads to generation of Factor VIIa in vivo. In another embodiment, the invention relates to a method of treating hemophilia in an individual who has developed an inhibitor of Factor IX, comprising administering to the individual an effective amount of a DNA vector encoding modified Factor VII 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 DNA vector comprising 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 DNA vector comprising 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 comprising DNA vectors encoding a modified Factor VII, wherein the modified Factor VII leads to generation of Factor VIIa in vivo is also encompassed by the present invention. In one embodiment, the modified Factor VII comprises an amino acid sequence which codes for a signal for precursor cleavage by furin at the activation cleavage site of the modified Factor VII.

The present invention also relates to an expression vector comprising nucleic acid encoding a modified Factor VII, wherein the modified Factor VII leads to generation of Factor VIIa in vivo. In one embodiment, the nucleic acid sequence encodes an amino acid sequence which includes a signal for precursor cleavage by furin at the activation cleavage site of the modified Factor VII. In another embodiment, the nucleic acid construct comprises two expression constructs which encode a modified Factor VII wherein the first expression construct comprises amino acids 1-152 of human Factor VII and the second expression comprises amino acids 153-406 of human Factor VII and a leader sequence.

The present invention also relates to host cells comprising a DNA vector comprising a nucleic acid which encodes a modified Factor VII, wherein the modified Factor VII leads to generation of Factor VIIa in vivo. In one embodiment, the nucleic acid sequence encodes an amino acid sequence which includes a signal for precursor cleavage by furin at the activation cleavage site of the modified Factor VII. In another embodiment, the nucleic acid construct comprises two expression constructs which encode a modified Factor VII wherein the first expression construct comprises amino acids 1-152 of human Factor VII and the second expression comprises amino acids 153-406 of human Factor VII and a leader sequence.

Host cells comprising a DNA vector encoding a modified Factor VII in accordance with the present invention may be cultured ex vivo and administered to or implanted into an individual suffering from a blood coagulation defect or disease such as hemophilia A, hemophilia B or Factor VII deficiency.

Thus, the present invention provides for an alternative treatment of blood clotting defects, such as hemophilia A or hemophilia B, in an individual, particularly where the individual has developed inhibitors to conventional treatment (e.g., inhibitors against FVIII and/or FIX).

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates the intrinsic and extrinsic pathways for fibrin clot formation and the mechanism by which FVIIa can act.

FIG. 2 illustrates examples of mutations to the FVII amino acid sequence which can be engineered at the nucleotide level in order to create a furin cleavage site at the activation site of FVII.

FIG. 3 illustrates examples of mutations to the FVII amino acid sequence which can be engineered at the nucleotide level in order to create an SK1 cleavage site at the activation site of FVII.

FIG. 4 illustrates clotting time of 293 cells [FIG. 4A] and Hep3B cells FIG. 4B] untransfected, and transfected with FVII and FVIIa.

FIG. 5 illustrates clotting time in 293 cell supernates from normal, FVIII-.

FIG. 6 illustrates clotting time in a modified aPTT assay.



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stats Patent Info
Application #
US 20110034539 A1
Publish Date
02/10/2011
Document #
12566831
File Date
09/25/2009
USPTO Class
514 44 R
Other USPTO Classes
International Class
/
Drawings
9


Blood Coagulation
Hemophilia
Hemophilia B


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