RNA interference mediated inhibition of protein tyrosine phosphatase-1B (PTP-1B) gene expression using short interfering nucleic acid (siNA)
This invention relates to compounds, compositions, and methods useful for modulating protein tyrosine phosphatase-1B (PTP-1B) gene expression using short interfering nucleic acid (siNA) molecules. This invention also relates to compounds, compositions, and methods useful for modulating the expression and activity of other genes involved in pathways of PTP-1B gene expression and/or activity by RNA interference (RNAi) using small nucleic acid molecules. In particular, the instant invention features small nucleic acid molecules, such as short interfering nucleic acid (siNA), short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (miRNA), and short hairpin RNA (shRNA) molecules and methods used to modulate the expression of PTP-1B genes. Such small nucleic acid molecules are useful, for example, for treating, preventing, inhibiting, or reducing obesity, insulin resistance, diabetes (eg. type II and type I diabetes) in a subject or organism, and for any other disease, trait, or condition that is related to or will respond to the levels of PTP-1B in a cell or tissue, alone or in combination with other treatments or therapies.
1. A chemically modified short interfering nucleic acid (siNA) molecule, wherein:
a) the siNA comprises a sense strand and an antisense strand, each strand having one or more pyrimidine nucleotides and one or more purine nucleotides;
b) each strand is independently 18 to 27 nucleotides in length, and together comprise a duplex having between 17 and 23 base pairs;
c) the antisense strand is complementary to a Protein Tyrosine Phosphatase-1B (PTP-1B) RNA sequence comprising SEQ ID NO: 760;
d) a plurality of pyrimidine nucleotides present in the sense strand are 2′-deoxy-2′-fluoro pyrimidine nucleotides and a plurality of purine nucleotides present in the sense strand are 2′-deoxy purine nucleotides; and
(e) a plurality of pyrimidine nucleotides present in the antisense strand are 2′-deoxy-2′-fluoro pyrimidine nucleotides and a plurality of purine nucleotides present in the antisense strand are 2′-O-methyl-puine nucleotides.
2. The siNA molecule of claim 1 , wherein the sense strand has a cap at both 5′- and 3′-ends of the sense strand.
3. The siNA molecule of claim 1 , comprising a 3′-overhang on one or both strands.
4. The siNA of claim 1 , wherein the antisense strand has a phosphorothioate internucleotide linkage at the 3′end.
5. A chemically modified short interfering nucleic acid (siNA) molecule, wherein:
(a) the siNA molecule comprises a sense strand and an antisense strand, each strand having one or more pyrimidine nucleotides and one or more purine nucleotides;
(b) each strand is independently 18 to 27 nucleotides in length, and together comprise a duplex having between 17 and 23 base pairs;
(c) the antisense strand is complementary to a Protein Tyrosine Phosphatase-1B (PTP-1B) RNA sequence comprising SEQ ID NO:760;
(d) a plurality of the pyrimidine nucleotides present in the sense strand are 2′-deoxy-2′-fluoro pyrimidine nucleotides and a plurality of the purine nucleotides present in the sense strand are 2′-deoxy purine nucleotides; and,
(e) a plurality of pyrimidine nucleotides present in said antisense strand are 2′-deoxy-2′-fluoro pyrimidine nucleotides and a plurality of purine nucleotides present in the antisense strand are 2′-deoxypurine nucleotides.
6. The siNA molecule of claim 5 , wherein the antisense strand has a phosphorothioate internucleotide linkage at the 3′end.
7. A composition comprising the siNA molecule of claim 1 and a pharmaceutically acceptable carrier or diluent.