Compositions and methods for the treatment of hemophilia a

Abstract

Improved materials and methods for the treatment of Hemophilia A are provided.

1 - 10 . (canceled)  
     
     
         11 . A method of treating hemophilia in a patient in need thereof, comprising: 
 a) providing a vector comprising a nucleic acid sequence encoding a biologically active recombinant human factor VIII (FVIII), operably linked to expression control elements; and    b) administering said vector to said patient under conditions that result in the expression of a modified human FVIII protein at a level that provides a therapeutic effect in said patient.    
     
     
         12 . The method of  claim 11 , wherein said vector is selected from the group consisting of adenoviral-based vectors, adeno-associated viral vectors, retroviral vectors, and transposon-transposase vector systems.  
     
     
         13 . (canceled)  
     
     
         14 . (canceled)  
     
     
         15 . The method of  claim 11 , wherein said FVIII variant comprises two segments connected by at least one PACE-furin cleavage site, wherein said segments are selected from the group consisting of: 
 a) a first segment consisting of the sequence of amino acids 1 to 700 of SEQ ID NO: 2 and a second segment consisting of the sequence of amino acids 1690 to 2332 of SEQ ID NO: 2;    b) a first segment consisting of the sequence of amino acids 1 to 710 of SEQ ID NO: 2 and a second segment consisting of the sequence of amino acids 1690 to 2332 of SEQ ID NO: 2;    c) a first segment consisting of the sequence of amino acids 1 to 720 of SEQ ID NO: 2 and a second segment consisting of the sequence of amino acids 1690 to 2332 of SEQ ID NO: 2;    d) a first segment consisting of the sequence of amino acids 1 to 730 of SEQ ID NO: 2 and a second segment consisting of the sequence of amino acids 1690 to 2332 of SEQ ID NO: 2;    e) a first segment consisting of the sequence of amino acids 1 to 740 of SEQ ID NO: 2 and a second segment consisting of the sequence of amino acids 1700 to 2332 of SEQ ID NO: 2;    f) a first segment consisting of the sequence of amino acids 1 to 740 of SEQ ID NO: 2 and a second segment consisting of the sequence of amino acids 1710 to 2332 of SEQ ID NO: 2;    g) a first segment consisting of the sequence of amino acids 1 to 740 of SEQ ID NO: 2 and a second segment consisting of the sequence of amino acids 1720 to 2332 of SEQ ID NO: 2;    h) a first segment consisting of the sequence of amino acids 1 to 740 of SEQ ID NO: 2 and a second segment consisting of the sequence of amino acids 1730 to 2332 of SEQ ID NO: 2;    i) a first segment consisting of the sequence of amino acids 1 to 730 of SEQ ID NO: 2 and a second segment consisting of the sequence of amino acids 1700 to 2332 of SEQ ID NO: 2;    j) a first segment consisting of the sequence of amino acids 1 to 730 of SEQ ID NO: 2 and a second segment consisting of the sequence of amino acids 1710 to 2332 of SEQ ID NO: 2;    k) a first segment consisting of the sequence of amino acids 1 to 730 of SEQ ID NO: 2 and a second segment consisting of the sequence of amino acids 1720 to 2332 of SEQ ID NO: 2;    l) a first segment consisting of the sequence of amino acids 1 to 730 of SEQ ID NO: 2 and a second segment consisting of the sequence of amino acids 1730 to 2332 of SEQ ID NO: 2;    m) a first segment consisting of the sequence of amino acids 1 to 720 of SEQ ID NO: 2 and a second segment consisting of the sequence of amino acids 1700 to 2332 of SEQ ID NO: 2;    n) a first segment consisting of the sequence of amino acids 1 to 720 of SEQ ID NO: 2 and a second segment consisting of the sequence of amino acids 1710 to 2332 of SEQ ID NO: 2;    o) a first segment consisting of the sequence of amino acids 1 to 720 of SEQ ID NO: 2 and a second segment consisting of the sequence of amino acids 1720 to 2332 of SEQ ID NO: 2;    p) a first segment consisting of the sequence of amino acids 1 to 720 of SEQ ID NO: 2 and a second segment consisting of the sequence of amino acids 1730 to 2332 of SEQ ID NO: 2;    q) a first segment consisting of the sequence of amino acids 1 to 710 of SEQ ID NO: 2 and a second segment consisting of the sequence of amino acids 1700 to 2332 of SEQ ID NO: 2;    r) a first segment consisting of the sequence of amino acids 1 to 710 of SEQ ID NO: 2 and a second segment consisting of the sequence of amino acids 1710 to 2332 of SEQ ID NO: 2;    s) a first segment consisting of the sequence of amino acids 1 to 710 of SEQ ID NO: 2 and a second segment consisting of the sequence of amino acids 1720 to 2332 of SEQ ID NO: 2;    t) a first segment consisting of the sequence of amino acids 1 to 710 of SEQ ID NO: 2 and a second segment consisting of the sequence of amino acids 1730 to 2332 of SEQ ID NO: 2;    u) a first segment consisting of the sequence of amino acids 1 to 700 of SEQ ID NO: 2 and a second segment consisting of the sequence of amino acids 1700 to 2332 of SEQ ID NO: 2;    v) a first segment consisting of the sequence of amino acids 1 to 700 of SEQ ID NO: 2 and a second segment consisting of the sequence of amino acids 1710 to 2332 of SEQ ID NO: 2;    w) a first segment consisting of the sequence of amino acids 1 to 700 of SEQ ID NO: 2 and a second segment consisting of the sequence of amino acids 1720 to 2332 of SEQ ID NO: 2; and    x) a first segment consisting of the sequence of amino acids 1 to 700 of SEQ ID NO: 2 and a second segment consisting of the sequence of amino acids 1730 to 2332 of SEQ ID NO: 2;    wherein said FVIII variant lacks amino acids 1648 to 1689 of SEQ ID NO: 2.