Adeno-associated virus factor VIII vectors, associated viral particles and therapeutic formulations comprising the same
AssigneeBiomarin Pharmaceutical Inc.
InventorsStuart Bunting, Peter Cameron Colosi, Erno Pungor
Life of this patent
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Abstract
The invention provides adeno-associated virus (AAV) Factor VIII (FVIII)-encoding/expressing vectors and virus, including AAV FVIII vectors with high expression activity and AAV FVIII vectors that express full-length or truncated functional FVIII protein. The invention also relates to methods of making the herein described AAV FVIII vectors, recombinant AAV FVIII virus particles comprising or expressing such vectors, associated pharmaceutical formulations comprising the same and therapeutic uses thereof.
Claims25
A method of treating a subject suffering from hemophilia A comprising administering a pharmaceutical formulation to said subject by intravenous administration,
- wherein the pharmaceutical formulation comprises a recombinant AAV-FVIII virus, sodium phosphate dibasic at a concentration of from about 0.1 mg/ml to about 3 mg/ml, sodium phosphate monobasic monohydrate at a concentration of from about 0.1 mg/ml to about 3 mg/ml, sodium chloride at a concentration of from about 1 mg/ml to about 20 mg/ml, mannitol at a concentration of from about 5 mg/ml to about 40 mg/ml, and poloxamer 188 at a concentration of from about 0.1 mg/ml to about 4 mg/ml,
- wherein the recombinant AAV-FVIII virus comprises a vector comprising an AAV2 5′ inverted terminal repeat (ITR), a liver specific transcriptional regulatory region, a FVIII nucleic acid sequence that encodes a functionally active FVIII protein, a polyadenylation sequence, an AAV2 3′ ITR, and optionally one or more introns inserted into the FVIII coding sequence or between the promoter and the FVIII coding sequence, wherein the functionally active FVIII coding region nucleic acid sequence comprises nucleotides 403-4776 of SEQ ID NO:
- 1 wherein expression of the FVIII from the recombinant AAV-FVIII in the subject treats the hemophilia A.
A method of increasing Factor VIII protein levels in a subject in need thereof comprising administering a pharmaceutical formulation to said subject by intravenous administration,
- wherein the pharmaceutical formulation comprises a recombinant AAV-FVIII virus, sodium phosphate dibasic at a concentration of from about 0.1 mg/ml to about 3 mg/ml, sodium phosphate monobasic monohydrate at a concentration of from about 0.1 mg/ml to about 3 mg/ml, sodium chloride at a concentration of from about 1 mg/ml to about 20 mg/ml, mannitol at a concentration of from about 5 mg/ml to about 40 mg/ml, and poloxamer 188 at a concentration of from about 0.1 mg/ml to about 4 mg/ml,
- wherein the recombinant AAV-FVIII virus comprises a vector comprising an AAV2 5′ ITR, a liver specific transcriptional regulatory region, a functionally active FVIII coding region FVIII nucleic acid sequence that encodes a functionally active FVIII protein, a polyadenylation sequence, an AAV2 3′ ITR, and optionally one or more introns inserted into the FVIII coding sequence or between the promoter and the FVIII coding sequence, wherein the functionally active FVIII coding region comprises nucleotides 403-4776 of SEQ ID NO:
- 1 wherein expression of the FVIII from the recombinant AAV-FVIII in the subject increases the level of FVIII in the subject.
A method of treating a subject suffering from hemophilia A comprising the steps of (i) determining the absence of anti-AAV capsid antibodies in the serum of said subject, and (ii) administering to said subject a pharmaceutical formulation by intravenous administration,
- wherein the pharmaceutical formulation comprises a recombinant AAV-FVIII virus, sodium phosphate dibasic at a concentration of from about 0.1 mg/ml to about 3 mg/ml, sodium phosphate monobasic monohydrate at a concentration of from about 0.1 mg/ml to about 3 mg/ml, sodium chloride at a concentration of from about 1 mg/ml to about 20 mg/ml, mannitol at a concentration of from about 5 mg/ml to about 40 mg/ml, and poloxamer 188 at a concentration of from about 0.1 mg/ml to about 4 mg/ml,
- wherein the recombinant AAV-FVIII virus comprises a vector comprising an AAV2 5′ ITR, a liver specific transcriptional regulatory region, a functionally active FVIII coding region FVIII nucleic acid sequence that encodes a functionally active FVIII protein, a polyadenylation sequence, an AAV2 3′ ITR, and optionally one or more introns inserted into the FVIII coding sequence or between the promoter and the FVIII coding sequence, wherein the functionally active FVIII coding region comprises nucleotides 403-4776 of SEQ ID NO:
- 1 wherein expression of the FVIII from the recombinant AAV-FVIII in the subject treats the hemophilia A.
A method of treating a subject suffering from hemophilia A comprising the steps of (i) administering to said subject a pharmaceutical formulation by intravenous administration,
- wherein the pharmaceutical formulation comprises a recombinant AAV-FVIII virus, sodium phosphate dibasic at a concentration of from about 0.1 mg/ml to about 3 mg/ml, sodium phosphate monobasic monohydrate at a concentration of from about 0.1 mg/ml to about 3 mg/ml, sodium chloride at a concentration of from about 1 mg/ml to about 20 mg/ml, mannitol at a concentration of from about 5 mg/ml to about 40 mg/ml, and poloxamer 188 at a concentration of from about 0.1 mg/ml to about 4 mg/ml,
- wherein the recombinant AAV-FVIII virus comprises a vector comprising an AAV2 5′ ITR, a liver specific transcriptional regulatory region, a functionally active FVIII coding region FVIII nucleic acid sequence that encodes a functionally active FVIII protein, a polyadenylation sequence, an AAV2 3′ ITR, and optionally one or more introns inserted into the FVIII coding sequence or between the promoter and the FVIII coding sequence, wherein the functionally active FVIII coding region comprises nucleotides 403-4776 of SEQ ID NO:
- 1,
- (ii) after administration of said recombinant AAV FVIII virus, determining the absence or the presence of anti-AAV capsid antibodies in the serum of said subject wherein expression of the FVIII from the recombinant AAV-FVIII in the subject treats the hemophilia A.
Dependencies are inferred from the claim text.