Abstract: The present application, in some embodiments, is directed to a polynucleotide including: (a) a first nucleic acid molecule including a sequence of a human endogenous Bruton's tyrosine kinase (BTK) promoter; and (b) a second nucleic acid molecule including a codon optimized sequence encoding a BTK or a functional analog thereof. Further provided are an expression vector, a cell, and a composition, all of which include the polynucleotide of the invention, and a method of using same, such as for treating X-linked Agammaglobulinemia (XLA) in a subject in need thereof.

Abstract: The invention provides expression cassettes. In certain embodiments, an expression cassette comprises (a) a regulatory element at least 90% identical to the sequence of any of SEQ ID NOs:2-67, and (b) a nucleic acid sequence encoding a Factor VIII protein having a B domain deletion (FVIII-BDD), where the nucleic acid sequence of (a) is at least 90% identical to the sequence of SEQ ID NO:77, where the regulatory element is operably linked to the nucleic acid sequence, and where no intron is present between the regulatory element and the nucleic acid sequence encoding FVIII-BDD, or where no more than 0-107 nucleotides of untranslated nucleic acid is between the regulatory element and the nucleic acid sequence encoding FVIII-BDD. In certain embodiments, expression cassettes contain sequence elements having CpG(s) substituted with CpT, CpA, TpG, or ApG at the same position(s) or has CpG reduced nucleic acid sequences.

Abstract: The present application, in some embodiments, is directed to a polynucleotide including: (a) a first nucleic acid molecule including a sequence of a human endogenous Bruton's tyrosine kinase (BTK) promoter; and (b) a second nucleic acid molecule including a codon optimized sequence encoding a BTK or a functional analog thereof. Further provided are an expression vector, a cell, and a composition, all of which include the polynucleotide of the invention, and a method of using same, such as for treating X-linked Agammaglobulinemia (XLA) in a subject in need thereof.

Abstract: The present application, in some embodiments, is directed to a polynucleotide including: (a) a first nucleic acid molecule including a sequence of a human endogenous Bruton's tyrosine kinase (BTK) promoter; and (b) a second nucleic acid molecule including a codon optimized sequence encoding a BTK or a functional analog thereof. Further provided are an expression vector, a cell, and a composition, all of which include the polynucleotide of the invention, and a method of using same, such as for treating X-linked Agammaglobulinemia (XLA) in a subject in need thereof.

Abstract: Factor VIII variants and methods of use thereof are disclosed. In particular embodiments, Factor VIII variants are expressed more efficiently by cells over wild-type Factor VIII proteins, are secreted at increased levels by cells over wild-type Factor VIII proteins, exhibit enhanced activity over wild-type Factor VIII proteins and are packaged more efficiently into viral vectors.

Abstract: Factor VIII variants and methods of use thereof are disclosed. In particular embodiments, Factor VIII variants are expressed more efficiently by cells over wild-type Factor VIII proteins, are secreted at increased levels by cells over wild-type Factor VIII proteins, exhibit enhanced activity over wild-type Factor VIII proteins and are packaged more efficiently into viral vectors.