Reduced size self-delivering RNAI compounds
The present invention relates to methods for in vivo administration of sd-rxRNA molecules.
1. A method for inhibiting the expression of a target gene of a mammal, comprising
administering to a mammal an sd-rxRNA® in an effective amount to inhibit the expression of a target gene of the mammal, wherein the sd-rxRNA® comprises a guide strand and a passenger strand, wherein the sd-rxRNA® includes a double stranded region and a single stranded region wherein the double stranded region is from 8-15 nucleotides long, wherein the single stranded region is at the 3′ end of the guide strand and is 4-12 nucleotides long, wherein the single stranded region contains 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 phosphorothioate modifications, wherein at least 40% of the nucleotides are modified, and wherein at least two Us and/or Cs include a hydrophobic modification comprising an octyl or a pyridyl amide modification.
2. The method of claim 1 , wherein at least 60% of the nucleotides are modified.
3. The method of claim 1 , wherein the modifications include at least one 2′F or 2′O methyl modification.
4. The method of claim 1 , wherein a plurality of Us and/or Cs include a hydrophobic modification, and wherein each of the hydrophobic modifications is an octyl or a pyridyl amide modification.
5. The method of claim 1 , wherein the sd-rxRNA® is attached to a linker.
6. The method of claim 5 , wherein the linker is protonatable.
7. The method of claim 1 , wherein the sd-rxRNA® is linked at the 3′ end to cholesterol, and/or wherein the guide strand contains at least 5 phosphorothioate modifications.
8. The method of claim 1 , wherein the sd-rxRNA® is delivered to the liver, heart, brain, spinal cord, lung or fat.
9. The method of claim 1 , wherein the sd-rxRNA® is delivered to a tumor, optionally wherein the sd-rxRNA® is administered to the tumor through intravenous administration or wherein the sd-rxRNA® is administered to the tumor through direct injection into the tumor.
10. The method of claim 1 , wherein the sd-rxRNA is administered subcutaneously, is administered through intravenous administration, or is administered by intrathecal delivery.