The present disclosure provides antisense oligonucleotides, compositions, and methods that target ATP7B exon 6 or a flanking intron, thereby modulating splicing of ATP7B pre-mRNA to increase the level of ATP7B mRNA molecules having exon 6, e.g., to provide a therapy for Wilson disease. The present disclosure provides an antisense oligonucleotide including a nucleobase sequence at least 70% complementary to an ATP7B target sequence in exon 6, a 5′-flanking intron, a 3′-flanking intron, or a combination of exon 6 and the 5′-flanking or 3′-flanking intron.

The invention relates to a nucleic acid construct carrying ATP7B protein, an expression vector and a viral particle comprising the nucleic acid construct, and their use for treatment of Wilson's disease and other conditions caused by a deficiency or dysfunction of ATP7B protein. An AAV vector devised according to the invention significantly reduced urine Cu excretion, and liver Cu content in Wilson's disease mice treated with the vector, while ceruloplasmin activity was significantly restored. On the other hand, the administration of the vector resulted in the normalization of serum transaminases levels and of liver histology, together with a marked reduction of the inflammatory infiltrate.

The invention relates to nucleic acid constructs and gene therapy vectors that comprise an ATP7B variant for use in the treatment of conditions associated with a deficiency or dysfunction of Copper-transporting ATPase 2, and particularly of Wilson's disease. An AAV vector devised according to the invention significantly reduced urine Cu excretion, and liver Cu content in Wilson's disease mice treated with the vector, while ceruloplasmin activity was significantly restored. On the other hand, the administration of the vector resulted in the normalization of serum transaminases' levels and of liver histology, together with a marked reduction of the inflammatory infiltrate.

Provided herein are nucleic acid molecules and vectors comprising variant copper transporting ATPase 2 (ATP7B) nucleic acid sequences. Such sequences have been optimized for expression in mammalian cells, liver cells, and/or from an adeno associated viral vector (AAV), including truncated and/or codon optimized variants. Also provided are viral vectors comprising such ATP7B variant nucleic acid sequences, and methods of use thereof for treating disorders associated with an ATP7B deficiency, such as Wilsons disease.

The invention relates to nucleic acid constructs and gene therapy vectors that comprise an ATP7B variant for use in the treatment of conditions associated with a deficiency or dysfunction of Copper-transporting ATPase 2, and particularly of Wilson's disease. An AAV vector devised according to the invention significantly reduced urine Cu excretion, and liver Cu content in Wilson's disease mice treated with the vector, while ceruloplasmin activity was significantly restored. On the other hand, the administration of the vector resulted in the normalization of serum transaminases' levels and of liver histology, together with a marked reduction of the inflammatory infiltrate.

Disclosed herein are codon-optimized nucleic acids encoding a reduced-size ATP7A protein. Also disclosed are vectors and recombinant viruses (such as recombinant adeno-associated viruses) including the codon-optimized nucleic acids encoding the reduced-size ATP7A protein and compositions including the disclosed vectors and viruses. Further disclosed herein are methods of treating copper transport disorders, for example by administering a disclosed nucleic acid, vector, or recombinant virus to a subject with a copper transport disorder, such as Menkes disease, occipital horn syndrome, or ATP7A-related distal motor neuropathy.

Disclosed herein are codon-optimized nucleic acids encoding a reduced-size ATP7A protein. Also disclosed are vectors and recombinant viruses (such as recombinant adeno-associated viruses) including the codon-optimized nucleic acids encoding the reduced-size ATP7A protein and compositions including the disclosed vectors and viruses. Further disclosed herein are methods of treating copper transport disorders, for example by administering a disclosed nucleic acid, vector, or recombinant virus to a subject with a copper transport disorder, such as Menkes disease, occipital horn syndrome, or ATP7A-related distal motor neuropathy.

The present disclosure provides antisense oligonucleotides, compositions, and methods that target ATP7B exon 6 or a flanking intron, thereby modulating splicing of ATP7B pre-mRNA to increase the level of ATP7B mRNA molecules having exon 6, e.g., to provide a therapy for Wilson disease. The present disclosure provides an antisense oligonucleotide including a nucleobase sequence at least 70% complementary to an ATP7B target sequence in exon 6, a 5-flanking intron, a 3-flanking intron, or a combination of exon 6 and the 5-flanking or 3-flanking intron.

Disclosed herein are codon-optimized nucleic acids encoding a reduced-size ATP7A protein. Also disclosed are vectors and recombinant viruses (such as recombinant adeno-associated viruses) including the codon-optimized nucleic acids encoding the reduced-size ATP7A protein and compositions including the disclosed vectors and viruses. Further disclosed herein are methods of treating copper transport disorders, for example by administering a disclosed nucleic acid, vector, or recombinant virus to a subject with a copper transport disorder, such as Menkes disease, occipital horn syndrome, or ATP7A-related distal motor neuropathy.

Disclosed herein are codon-optimized nucleic acids encoding a reduced-size ATP7A protein. Also disclosed are vectors and recombinant viruses (such as recombinant adeno-associated viruses) including the codon-optimized nucleic acids encoding the reduced-size ATP7A protein and compositions including the disclosed vectors and viruses. Further disclosed herein are methods of treating copper transport disorders, for example by administering a disclosed nucleic acid, vector, or recombinant virus to a subject with a copper transport disorder, such as Menkes disease, occipital horn syndrome, or ATP7A-related distal motor neuropathy.