Compositions and methods for treatment of kidney disease
Described herein are antisense oligonucleotides, vectors, and related compositions and methods for increasing expression of PKD1 mRNA and Polycystin 1 protein and uses thereof for the treatment of autosomal dominant polycystic kidney disease (ADPKD).
1 . An antisense oligonucleotide, wherein the nucleotide sequence of the antisense oligonucleotide consists of SEQ ID NO:47, wherein the antisense oligonucleotide is a phosphorodiamidate morpholino oligonucleotide.
2 . A pharmaceutical composition comprising the antisense oligonucleotide according to claim 1 , and a pharmaceutically acceptable excipient.
3 . A method for treating autosomal dominant polycystic kidney disease (ADPKD) in a human subject in need thereof, wherein the ADPKD is caused by a mutation in a single copy of a Polycystin 1, Transient Receptor Potential Channel Interacting (PKD1) gene, wherein the subject also has an unmutated copy of the PKD1, the method comprising administering to the human subject a therapeutically effective amount of the pharmaceutical composition according to claim 2 , wherein the antisense oligonucleotide binds to a targeted portion of the 3′ untranslated region (UTR) of a mRNA encoded by the unmutated copy of the PKD1 gene that comprises in the 3′UTR a functional binding site for miR-17 family miRNAs, whereby binding of a miR-17 family member miRNA to the binding site is reduced.
4 . The antisense oligonucleotide according to claim 1 , wherein the antisense oligonucleotide further comprises a cell-penetrating peptide (CPP) covalently linked to the antisense oligonucleotide.
5 . The antisense oligonucleotide according to claim 4 , wherein the amino acid sequence of the CPP comprises SEQ ID NO:352.
6 . The antisense oligonucleotide according to claim 5 , wherein the amino acid sequence of the CPP consists of SEQ ID NO:352.
7 . The antisense oligonucleotide according to claim 5 , wherein any amino acid other than glycine is a D-amino acid.
8 . The antisense oligonucleotide according to claim 4 , wherein the CPP is linked to the 5′ end of the antisense oligonucleotide.
9 . A pharmaceutical composition comprising the antisense oligonucleotide according to claim 4 , and a pharmaceutically acceptable excipient.
10 . A method for treating ADPKD in a human subject in need thereof, wherein the ADPKD is caused by a mutation in a single copy of a PKD1 gene, wherein the subject also has an unmutated copy of the PKD1 gene, the method comprising administering to the human subject a therapeutically effective amount of the pharmaceutical composition according to claim 9 , wherein the antisense oligonucleotide binds to a targeted portion of the 3′ UTR of a mRNA encoded by the unmutated copy of the PKD1 gene that comprises in the 3′UTR a functional binding site for miR-17 family miRNAs, whereby binding of a miR-17 family member miRNA to the binding site is reduced.