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Publication Number
US-11753461-B2
Publication Date
2023-09-12
Expiration Date
Abstract
The present disclosure provides codon optimized Factor VIII sequences, vectors, and host cells comprising codon optimized Factor VIII sequences, polypeptides encoded by codon optimized Factor VIII sequences, and methods of producing such polypeptides. The present disclosure also provides methods of treating bleeding disorders such as hemophilia comprising administering to the subject a codon optimized Factor VIII nucleic acid sequence or the polypeptide encoded thereby.
Core Innovation
The disclosed invention comprises isolated nucleic acid molecules encoding a polypeptide with FVIII activity, including B domain-deleted variants and fusion proteins with heterologous moieties. Claimed sequences comprise nucleotides 58–2277 and 2320–4374 of SEQ ID NO: 71 or SEQ ID NO: 72, which are engineered to alter codon usage and reduce inhibitory sequence motifs. These nucleic acids are incorporated into vectors, including lentiviral vectors, to increase FVIII expression and treat hemophilia A or other bleeding disorders.
Experimental descriptions report increased and sustained plasma FVIII activity following lentiviral vector administration in hemophilia A models. Evaluated constructs include codon-optimized variants such as coFVIII-52XTEN and coFVIII-6XTEN, which demonstrate elevated activity relative to controls alongside normalized coagulation parameters. These findings support host-cell expression systems and vectors configured to improve recombinant FVIII yields and therapeutic efficacy.
Claims Coverage
The claims identify two inventive features across two independent claims directed to isolated nucleic acid molecules encoding a polypeptide with FVIII activity.
Nucleic acid comprising specified regions of SEQ ID NO: 71
An isolated nucleic acid molecule comprising a nucleotide sequence encoding a polypeptide with FVIII activity, wherein the sequence comprises nucleotides 58–2277 and 2320–4374 of SEQ ID NO: 71, with dependent claims encompassing vectors, including lentiviral vectors, and methods for increasing FVIII expression.
Nucleic acid comprising SEQ ID NO: 72
An isolated nucleic acid molecule comprising a nucleotide sequence encoding a polypeptide with FVIII activity and comprising SEQ ID NO: 72, with dependent claims extending to vectors, including lentiviral vectors, methods for increasing FVIII expression, and treatment of hemophilia A in a mammalian subject.
The two independent claims define distinct sequence-defined nucleic acid alternatives encoding FVIII-active polypeptides, with dependent claims extending to vectors including lentiviral vectors, expression-increasing methods, and the treatment of hemophilia A.
Stated Advantages
Increased expression of a polypeptide with FVIII activity in a mammalian subject relative to a reference nucleic acid molecule comprising SEQ ID NO: 16.
Improved FVIII expression and recombinant protein yield achieved through codon optimization and reduction of inhibitory sequence elements.
Sustained plasma FVIII activity following lentiviral treatment, with activity levels for coFVIII-52XTEN and coFVIII-6XTEN substantially above wild-type or non-optimized BDD-FVIII.
Post-treatment thromboelastography results falling within normal physiological ranges.
Documented Applications
Treatment of hemophilia A and other bleeding or hemostatic disorders in a mammalian subject using a vector comprising the claimed nucleic acid molecule.
Increasing expression of a polypeptide with FVIII activity in a mammalian subject using a vector comprising the claimed nucleic acid molecule.
Use in vectors, including lentiviral vectors, and host-cell expression systems for recombinant FVIII protein yield and production.
Therapeutic use in gene therapy and bypass therapy.
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