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Publication Number
US-12275970-B2
Publication Date
2025-04-15
Expiration Date
Abstract
The present invention provides codon optimized Factor IX sequences, vectors and host cells comprising codon optimized Factor IX sequences, polypeptides encoded by codon optimized Factor IX sequences, and methods of producing such polypeptides. The present invention also provides methods of treating bleeding disorders such as hemophilia comprising administering to the subject a codon optimized Factor IX nucleic acid sequence or the polypeptide encoded thereby.
Core Innovation
The disclosed subject matter relates to Factor IX (FIX) nucleic acids and polypeptides with Factor IX activity for use in hemophilia B (Christmas disease). The nucleic acids are optimized nucleotide sequences that encode a polypeptide with Factor IX activity and are designed for increased expression relative to a reference nucleic acid molecule comprising SEQ ID NO: 2.
The nucleic acids include codon optimization features and sequence composition changes, including increased human codon adaptation index and increased G/C content. Sequence elements are removed or reduced that include destabilizing elements, cis-acting negative regulatory/splice motifs, poly-T and poly-A tracts, antiviral motifs, and repeat sequences, including AU-rich elements and direct, inverted, or dyad repeat sequences.
The document further describes optional heterologous nucleotide sequences that encode heterologous amino acid sequences for half-life extension or expression-related performance, including immunoglobulin constant regions or a portion thereof, Fc or FcRn-binding partners, transferrin, albumin or albumin-binding moieties, XTEN, PAS, CTP, and HAP. It also discusses transcription control sequences and operable promoter linkage, including vectors, host cells, recombinant production and secretion, and administration for gene therapy.
Claims Coverage
The independent claim coverage centers on one method claim, clm-00001, directed to administering an isolated nucleic acid molecule or a vector encoding FIX to increase expression of a polypeptide with Factor IX activity in a subject. The inventive features include defined sequence-identity relationships to multiple SEQ IDs, increased expression relative to a reference nucleic acid molecule comprising SEQ ID NO: 2, and nucleic-acid optimization parameters.
Administering a FIX-encoding nucleic acid or vector to increase expression
Administering to a subject in need thereof an isolated nucleic acid molecule or a vector comprising the isolated nucleic acid molecule, wherein the isolated nucleic acid molecule comprises a nucleotide sequence that encodes a polypeptide with Factor IX activity and increases expression of the polypeptide relative to a reference nucleic acid molecule comprising SEQ ID NO: 2.
Defined nucleotide sequence identity to specified SEQ IDs for FIX activity
Using a nucleotide sequence selected from sequences at least 85% identical to SEQ ID NO: 1, at least 95% identical to SEQ ID NO: 54, at least 96% identical to SEQ ID NO: 55, at least 99% identical to SEQ ID NO: 56, and at least 94% identical to SEQ ID NO: 57 and SEQ ID NO: 58, where the nucleotide sequence encodes a polypeptide with Factor IX activity.
Codon adaptation and G/C content while removing specific sequence elements
Providing a nucleotide sequence with increased human codon adaptation index and increased G/C content, and lacking or excluding specified destabilizing elements, specified splice site motifs, repeat sequences, specified antiviral motifs, poly-T sequences, and specified poly-A sequences, or any combination of these features.
Heterologous amino acid sequences for half-life extension
Including, in some embodiments, a heterologous nucleotide sequence that encodes a heterologous amino acid sequence comprising an immunoglobulin constant region or a portion thereof, transferrin, albumin, XTEN, PAS, CTP, or HAP.
Overall, the claims coverage focuses on administering optimized Factor IX-encoding nucleic acids or vectors that increase expression of a Factor IX activity polypeptide in a subject compared with a reference nucleic acid molecule comprising SEQ ID NO: 2, with defined sequence identities and optional heterologous sequences for half-life extension.
Stated Advantages
Increased expression of a polypeptide with Factor IX activity in a subject relative to a reference nucleic acid molecule comprising SEQ ID NO: 2.
Increased plasma Factor IX activity at 24 hours post administration relative to a subject administered the reference nucleic acid molecule comprising SEQ ID NO: 2 or a vector comprising the reference nucleic acid molecule.
Optimized nucleic acid sequences with increased human codon adaptation index and increased G/C content while removing or reducing destabilizing elements, cis-acting negative regulatory/splice motifs, poly-T/poly-A tracts, antiviral motifs, and repeat sequences.
Optional heterologous sequences for half-life extension.
Documented Applications
Treatment of bleeding disorders via administration of an isolated nucleic acid molecule or a vector comprising a FIX-encoding nucleotide sequence, with a stated example of increased plasma FIX activity at 24 hours post administration.
Gene therapy contexts using vectors to achieve endogenous Factor IX production.
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