Allelic variants of human factor viii

Abstract

Disclosed are compositions and methods related to Factor VIII.

We claim: 
     
         1 . A Factor VIII replacement preparation comprising an effective amount of purified Factor VIII (FVIII) having a haplotype selected from the group consisting of the H3 haplotype, H4 haplotype, H5 haplotype, and H6 haplotype,
 wherein each haplotype of the purified FVIII is enriched from plasma of a plurality of donors each having only the corresponding haplotypically-pure haplotype of FVIII, or   wherein the purified FVIII is a recombinant FVIII that is produced from cDNA that comprises SEQ ID NO: 3 for H3 haplotype, SEQ ID NO: 4 for H4 haplotype, SEQ ID NO: 5 for H5 haplotype, or SEQ ID NO: 6 for H6 haplotype.   
     
     
         2 . The FVIII replacement preparation of  claim 1 , wherein the purified FVIII comprises a polypeptide having the amino acid sequence of SEQ ID NO: 22, having the H4 haplotype. 
     
     
         3 . The FVIII replacement preparation of  claim 1 , wherein the purified FVIII comprises a polypeptide having the amino acid sequence of SEQ ID NO: 23 having the H5 haplotype. 
     
     
         4 . The FVIII replacement preparation of  claim 1 , wherein the purified FVIII comprises a polypeptide having the amino acid sequence of SEQ ID NO: 24, having the H6 haplotype. 
     
     
         5 . The FVIII replacement preparation of  claim 1 , wherein the purified FVIII comprises a polypeptide having the amino acid sequence of SEQ ID NO: 21, having the H3 haplotype. 
     
     
         6 . The FVIII replacement preparation of  claim 1 , wherein the donors are African American or of African descent. 
     
     
         7 . The FVIII replacement preparation of  claim 6 , wherein the African American donors or donors of African descent are male and hemizygous for the gene encoding a specific haplotype Factor VIII or female and homozygous for the gene encoding a specific haplotype Factor VIII, wherein the specific haplotype Factor VIII is selected from H3, H4, and H5. 
     
     
         8 . The FVIII replacement preparation of  claim 1 , wherein the donors are Chinese American or of Chinese descent. 
     
     
         9 . The FVIII replacement preparation of  claim 8 , wherein Chinese American donors or donors of Chinese descent are male and hemizygous for the gene encoding haplotype 6 Factor VIII or female and homozygous for the gene encoding haplotype 6 Factor VIII. 
     
     
         10 . A method for treating a subject with hemophilia having a defective FVIII comprising administering to the subject with hemophilia a Factor VIII (FVIII) replacement preparation comprising an effective amount of a purified FVIII having a haplotype selected from the group consisting of the H3 haplotype, H4 haplotype, H5 haplotype, and H6 haplotype,
 wherein the FVIII haplotype of the subject and the administered purified FVIII are the same regardless of the type of FVIII mutation the subject has.   
     
     
         11 . The method of  claim 10 , wherein the purified FVIII has the H3 haplotype protein comprising a polypeptide having the amino acid sequence of SEQ ID NO: 21 and the subject has H3 haplotype regardless of the type of FVIII mutation the subject has. 
     
     
         12 . The method of  claim 10 , wherein the purified FVIII has the H4 haplotype protein comprising a polypeptide having the amino acid sequence of SEQ ID NO: 22 and the subject has H4 haplotype regardless of the type of FVIII mutation the subject has. 
     
     
         13 . The method of  claim 10 , wherein the purified FVIII has the H5 haplotype protein comprising a polypeptide having the amino acid sequence of SEQ ID NO: 23 and the subject has H5 haplotype regardless of the type of FVIII mutation the subject has. 
     
     
         14 . The method of  claim 10 , wherein the purified FVIII has the H6 haplotype protein comprising a polypeptide having the amino acid sequence of SEQ ID NO: 24 and the subject has H6 haplotype regardless of the type of FVIII mutation the subject has. 
     
     
         15 . The method of  claim 10 , wherein each haplotype of the purified FVIII is enriched from plasma of a plurality of donors each having only the corresponding haplotypically-pure haplotype of FVIII, or wherein the purified FVIII is a recombinant FVIII that is produced from cDNA that comprises SEQ ID NO: 3 for H3 haplotype, SEQ ID NO: 4 for H4 haplotype, SEQ ID NO: 5 for H5 haplotype, or SEQ ID NO: 6 for H6 haplotype. 
     
     
         16 . The method of  claim 10 , further comprising determining the haplotype of the subject regardless of the type of FVIII mutation the subject has. 
     
     
         17 . The method of  claim 10 , wherein the defective FVIII of the subject has deletions, inversions, and/or nonsense mutations. 
     
     
         18 . The method of  claim 10 , wherein the defective FVIII of the subject has an intron-22 inversion. 
     
     
         19 . The method of  claim 10 , wherein the subject is African American or of African descent having a defective H3, H4, or H5 haplotype FVIII. 
     
     
         20 . The method of  claim 10 , wherein the subject is Chinese American or of Chinese descent having a defective H6 haplotype FVIII.