Reduced size self-delivering RNAi compounds

1. An isolated double stranded nucleic acid molecule comprising a guide strand and a passenger strand,

wherein the isolated double stranded nucleic acid molecule 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 of the isolated double stranded nucleic acid molecule are modified, wherein a hydrophobic conjugate is attached to the isolated double stranded nucleic acid molecule, and wherein the isolated double stranded nucleic acid molecule does not form a hairpin.

2. The isolated double stranded nucleic acid molecule of claim 1 , wherein the double stranded region is 11, 12, 13, or 14 nucleotides long and/or wherein the single stranded region is at least 6 or at least 7 nucleotides long.

3. The isolated double stranded nucleic acid molecule of claim 1 , wherein each nucleotide within the single stranded region has a phosphorothioate modification.

4. The isolated double stranded nucleic acid molecule of claim 1 , wherein at least one of the nucleotides of the isolated double stranded nucleic acid molecule that is modified comprises a 2′ O-methyl or a 2′-fluoro modification and/or wherein at least one of the nucleotides of the isolated double stranded nucleic acid molecule that is modified comprises a hydrophobic modification.

5. The isolated double stranded nucleic acid molecule of claim 1 , wherein the guide strand of the double stranded nucleic acid molecule exhibits complementarity to a gene encoding for Osteopontin (SPP1), SOD1 or MAP4K4, optionally wherein the guide strand comprises SEQ ID NO:170, SEQ ID NO:40 or SEQ ID NO:25.

6. An isolated asymmetric nucleic acid molecule comprising:

a first polynucleotide wherein the first polynucleotide is complementary to a second polynucleotide and a target gene; and

a second polynucleotide,

wherein the second polynucleotide is at least 6 nucleotides shorter than the first polynucleotide, wherein the first polynucleotide includes a single stranded region of 6, 7, 8, 9, 10, 11 or 12 nucleotides, wherein the single stranded region of the first polynucleotide contains 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 phosphorothioate modifications, wherein the asymmetric nucleic acid molecule also includes a double stranded region of 8-15 nucleotides long, wherein at least 50% of C and U nucleotides in the double stranded region are 2′ O-methyl modified or 2′-fluoro modified, and wherein a hydrophobic conjugate is attached to the asymmetric nucleic acid molecule.

7. The isolated asymmetric nucleic acid molecule of claim 6 , wherein the single stranded region is 6 or 7 nucleotides long and/or wherein each nucleotide within the single stranded region has a phosphorothioate modification.

8. The isolated asymmetric nucleic acid molecule of claim 6 , wherein each of the first polynucleotide and the second polynucleotide has a 5′ end and a 3′ end, wherein the hydrophobic conjugate is attached to:

i) the 3′ end of the second polynucleotide;

ii) the 3′ end of the first polynucleotide; or

iii) the 5′ end of the second polynucleotide.

9. An isolated double stranded nucleic acid molecule comprising:

a guide strand of 17-21 nucleotides in length that has complementarity to a target gene, and a passenger strand of 8-16 nucleotides in length,

wherein the isolated double stranded nucleic acid molecule includes a double stranded region of 8-15 nucleotides long and a single stranded region, wherein the guide strand and the passenger strand form the double stranded nucleic acid molecule having the double stranded region and the single stranded region, wherein the single stranded region is at the 3′ end of the guide strand and is 4-12 nucleotides in length, wherein the single stranded region comprises 2-12 phosphorothioate modifications, wherein at least 40% of the nucleotides of the isolated double stranded nucleic acid molecule are modified, and wherein the double stranded nucleic acid molecule is linked to a hydrophobic conjugate, and wherein the isolated double stranded nucleic acid molecule does not form a hairpin.

10. The isolated double stranded nucleic acid molecule of claim 9 , wherein the isolated double stranded nucleic acid molecule contains at least one hydrophobic base modification and wherein the hydrophobic base modification comprises a hydrophobic modification of a pyrimidine base, optionally at position 4 or 5, optionally wherein the hydrophobic base modification is selected from the group consisting of a phenyl, 4-pyridyl, 2-pyridyl, indolyl, isobutyl, tryptophanyl (C 8 H 6 N)CH 2 CH(NH 2 )CO), methyl, butyl, aminobenzyl, and naphthyl modification of a uridine or cytidine.

11. The isolated double stranded nucleic acid molecule of claim 9 , wherein the hydrophobic conjugate is a small molecule, optionally wherein the small molecule is a sterol-type molecule, optionally wherein the sterol-type molecule is cholesterol.

12. The isolated double stranded nucleic acid molecule of claim 9 , wherein the hydrophobic conjugate is attached to the double stranded nucleic acid molecule through a linker, optionally wherein the linker is a TEG linker.

13. A method for inhibiting the expression of a target gene in a mammalian cell, comprising contacting the mammalian cell with an isolated double stranded nucleic acid molecule comprising a guide strand and a passenger strand,

wherein the isolated double stranded nucleic acid molecule 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 of the guide strand contains 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 phosphorothioate modifications, wherein at least 40% of the nucleotides of the isolated double stranded nucleic acid molecule are modified, and wherein a hydrophobic conjugate is attached to the isolated double stranded nucleic acid molecule, and wherein the isolated double stranded nucleic acid molecule does not form a hairpin.

14. The method of claim 13 , wherein the double stranded region is 11, 12, 13, or 14 nucleotides long and/or wherein the single stranded region is at least 6 or at least 7 nucleotides long.

15. The method of claim 13 , wherein each nucleotide within the single stranded region has a phosphorothioate modification.

16. The method of claim 13 , wherein at least one of the nucleotides of the isolated double stranded nucleic acid molecule that is modified comprises a 2′ O-methyl or a 2′-fluoro modification and/or wherein at least one of the nucleotides of the isolated double stranded nucleic acid molecule that is modified comprises a hydrophobic modification.

17. The method of claim 13 , wherein the double stranded nucleic acid molecule exhibits complementarity to a gene encoding for Osteopontin (SPP1), SOD1 or MAP4K4, optionally wherein the guide strand comprises SEQ ID NO:170, SEQ ID NO:40 or SEQ ID NO:25.

18. The isolated double stranded nucleic acid molecule of claim 1 , wherein each of the guide strand and the passenger strand has a 5′ end and a 3′ end, and wherein the hydrophobic conjugate is attached to:

i) the 3′ end of the passenger strand;

ii) the 3′ end of the guide strand; or

iii) the 5′ end of the passenger strand.

19. The method of claim 13 , wherein each of the guide strand and the passenger strand has a 5′ end and a 3′ end, and wherein the hydrophobic conjugate is attached to:

i) the 3′ end of the passenger strand;

ii) the 3′ end of the guide strand; or

iii) the 5′ end of the passenger strand.