Short interfering nucleic acid (siNA) molecules containing a 2′ internucleoside linkage (3dT)

Patent metadata

Field	Value
Publication number	US-10738308-B2
Application number	US-201815863578-A
Country	US
Kind code	B2
Filing date	Jan 5, 2018
Priority date	Feb 22, 2013
Publication date	Aug 11, 2020
Grant date	Aug 11, 2020

Abstract

The present invention relates to RNAi molecules, and compositions thereof, comprising a 2′ internucleoside linkage connecting the nucleotide at position 1 and the nucleotide at position 2 at the 5′ end of the antisense strand. Specifically, the invention relates to single- and double-stranded short interfering nucleic acid (siNA) molecules that are capable of mediating RNA interference comprising 5′ modified nucleotides that comprise, among other potential modifications, a 2′ internucleoside linkage. The invention further relates to 5′ modified nucleotides used as reagents to generate the RNAi molecules of the invention and methods of using the disclosed RNAi molecules.

First claim

What is claimed is:

1. A double stranded short interfering nucleic acid (siNA) molecule capable of mediating RNA interference, comprising an antisense strand that is complementary to a nucleic acid target, wherein said antisense strand comprises a modified nucleotide at the first nucleotide position, wherein the modified nucleotide comprises a sugar ring, wherein carbon 5 of the sugar ring contains the following substituent (═CH)—P(═O)(OH) 2 , and wherein the modified nucleotide is a 2′-O-methyl nucleotide.

2. The short interfering nucleic acid of claim 1 , wherein the modified nucleotide comprises the following structure:

3. The siNA molecule of claim 1 , wherein the modified nucleotide comprises a heterocyclic base chosen from uracil, thymine, cytosine, 5-methylcytosine, adenine, or guanine.

4. The siNA molecule of claim 1 , wherein the modified nucleotide comprises an internucleo side linking group linking the modified nucleotide to the sugar moiety of an adjacent nucleotide of the siNA molecule, and wherein the internucleoside linking group is chosen from a phosphodiester internucleoside linking group or a phosphorothioate internucleoside linking group.

5. The siNA molecule of claim 1 , wherein the siNA molecule comprises one or more additional chemically-modified nucleotides.

6. The siNA molecule of claim 5 , wherein the one or more of the additional chemically-modified nucleotides is a 2′-O-methyl nucleotide.

7. The siNA molecule of claim 6 , wherein the one or more of the 2′-O-methyl nucleotides comprises a phosphorothioate internucleoside linking group.

8. The siNA molecule of claim 1 , which further comprises a conjugate.

9. The siNA molecule of claim 8 , wherein the conjugate comprises N-acetylgalactosamine.

10. The siNA molecule of claim 8 , wherein the conjugate comprises a tetra-N-acetylgalactosamine aminohexyl moiety.

11. The siNA molecule of claim 1 , which further comprises an inverted abasic nucleotide.

12. The siNA molecule of claim 1 , which comprises a sense strand, wherein the antisense strand and the sense strand are each independently 15 to 30 nucleotides in length.

13. The siNA molecule of claim 1 , further comprising one or more 3′-overhanging nucleotides on one or both strands.

14. A composition comprising the siNA molecule of claim 1 in a pharmaceutically acceptable carrier or diluent.

Assignees

• Sirna Therapeutics Inc

Inventors

• Chang Wonsuk
• Guidry Erin N
• Stanton Matthew G
• Zewge Daniel

Classifications

• C07H21/00 Primary

  Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids · CPC title

• C07H21/02

  with ribosyl as saccharide radical · CPC title

• C12N2310/11

  Antisense · CPC title

• C07H19/10

  with the saccharide radical esterified by phosphoric or polyphosphoric acids · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title