Treatment of atopic dermatitis and asthma using RNA complexes that target IL4Rα, TRPA1, or F2RL1
In certain aspects, provided herein are RNA complexes (e.g., asymmetric RNA complexes, such as asiRNAs or cell penetrating asiRNAs) that inhibit IL4Rα, TRPA1, and/or F2RL1 expression and are therefore useful for treating atopic dermatitis or asthma.
1. A nucleic acid complex for inducing RNA interference to inhibit expression of F2RL1 gene, the nucleic acid complex comprising an antisense strand and a sense strand, the antisense strand being 21 nucleotides in length and having the base sequence of SEQ ID NO: 421, and the sense strand being 15 to 17 nucleotides in length and having sequence complementarity to the antisense strand.
2. The nucleic acid complex of claim 1 , wherein the sense strand comprises the base sequence of SEQ ID NO: 420.
3. The nucleic acid complex of claim 1 , wherein the 5′ end of the antisense strand and the 3′ end of the sense strand form a blunt end.
4. The nucleic acid complex of claim 3 , wherein the RNA complex comprises a chemical modification.
5. The nucleic acid complex of claim 4 , wherein the chemical modification is a 2′-O-methylated nucleoside, a phosphorothioate bond, or a hydrophobic moiety.
6. The nucleic acid complex of claim 5 , wherein the hydrophobic moiety is a cholesterol moiety.
7. The nucleic acid complex of claim 5 , wherein the nucleic acid complex is a modified nucleic acid complex selected from:
(a) a nucleic acid complex comprising:
a sense strand of:
(SEQ ID NO: 642)
5′ mCUmGAmCCmUCmCUmCUmC*U*mG*U*cholesterol 3′;
and
an antisense strand of:
(SEQ ID NO: 643)
5′ ACAGAGAGGAGGUCmAmGC*C*A*A*G 3′;
(b) a nucleic acid complex comprising:
a sense strand of:
(SEQ ID NO: 644)
5′ mCUmGAmCCmUCmCUmCUmC*U*mG*U*cholesterol 3′;
and
an antisense strand of:
(SEQ ID NO: 645)
5′ ACAGAGAGGAGGUCmAmGmC*mC*A*A*G 3′;
(c) a nucleic acid complex comprising:
a sense strand of:
(SEQ ID NO: 646)
5′ mCUmGAmCCmUCmCUmCUmC*U*mG*U*cholesterol 3′;
and
an antisense strand of
(SEQ ID NO: 647)
5′ ACAGAGAGGAGGUCmAmGmC*mC*mA*mA*mG 3′;
(d) a nucleic acid complex comprising:
a sense strand of:
(SEQ ID NO: 672)
5′ mCUmGAmCCmUCmCUmCUmCU*mG*U*cholesterol 3′;
and
an antisense strand of
(SEQ ID NO: 673)
5′ ACAGAGAGGAGGUCmA*mG*mC*mC*A 3′;
(e) a nucleic acid complex comprising:
a sense strand of:
(SEQ ID NO: 674)
5′ mCUmGAmCCmUCmCUmCUmCU*mG*U*cholesterol 3′;
and
an antisense strand of
(SEQ ID NO: 675)
5′ ACAGAGAGGAGGUCmAmGmC*mC*A*A*G 3′;
(f) a nucleic acid complex comprising:
a sense strand of:
(SEQ ID NO: 676)
5′ mCUmGAmCCmUCmCUmCUmC*U*mG*U*cholesterol 3′;
and
an antisense strand of
(SEQ ID NO: 677)
5′ ACAGAGAGGAGGUCmA*mG*mC*mC*A 3′;
wherein m represents 2′-O-methyl RNA and * represents a phosphorothioate bond.
8. The nucleic acid complex of claim 7 , wherein the nucleic acid complex is capable of penetrating a cellular membrane of a cell in the absence of a delivery vehicle.
9. The nucleic acid complex of claim 1 , wherein the nucleic acid complex is for delivery to a cell comprising an A549, an epithelial cell or a keratinocyte.
10. The nucleic acid complex of claim 1 , wherein the nucleic acid complex is for delivery to a cell present in the skin or respiratory tract of a human subject.
11. A pharmaceutical composition comprising the nucleic acid complex of claim 1 and a pharmaceutically acceptable carrier.
12. The pharmaceutical composition of claim 11 , wherein the pharmaceutical composition is formulated for inhalation.
13. The pharmaceutical composition of claim 11 , wherein the pharmaceutical composition is formulated for topical administration.
14. The pharmaceutical composition of claim 11 , wherein the pharmaceutical composition is formulated for intradermal injection.
15. A method for treating a disorder or condition related to F2RL1 expression, comprising administering the nucleic acid complex of claim 1 to a subject in need thereof, wherein the disorder or condition is atopic dermatitis.
16. The method of claim 15 , comprising administering the nucleic acid complex topically.
17. The method of claim 15 , comprising administering the nucleic acid complex via intradermal injection.
18. The method of claim 15 , wherein the nucleic acid complex is a modified nucleic acid complex selected from:
(a) a nucleic acid complex comprising:
a sense strand of:
(SEQ ID NO: 642)
5′ mCUmGAmCCmUCmCUmCUmC*U*mG*U*cholesterol 3′;
and
an antisense strand of:
(SEQ ID NO: 643)
5′ ACAGAGAGGAGGUCmAmGC*C*A*A*G 3′;
(b) a nucleic acid complex comprising:
a sense strand of:
(SEQ ID NO: 644)
5′ mCUmGAmCCmUCmCUmCUmC*U*mG*U*cholesterol 3′;
and
an antisense strand of:
(SEQ ID NO: 645)
5′ ACAGAGAGGAGGUCmAmGmC*mC*A*A*G 3′;
(c) a nucleic acid complex comprising:
a sense strand of:
(SEQ ID NO: 646)
5′ mCUmGAmCCmUCmCUmCUmC*U*mG*U*cholesterol 3′;
and
an antisense strand of
(SEQ ID NO: 647)
5′ ACAGAGAGGAGGUCmAmGmC*mC*mA*mA*mG 3′;
(d) a nucleic acid complex comprising:
a sense strand of:
(SEQ ID NO: 672)
5′ mCUmGAmCCmUCmCUmCUmCU*mG*U*cholesterol 3′;
and
an antisense strand of
(SEQ ID NO: 673)
5′ ACAGAGAGGAGGUCmA*mG*mC*mC*A 3′;
(e) a nucleic acid complex comprising:
a sense strand of:
(SEQ ID NO: 674)
5′ mCUmGAmCCmUCmCUmCUmCU*mG*U*cholesterol 3′;
and
an antisense strand of
(SEQ ID NO: 675)
5′ ACAGAGAGGAGGUCmAmGmC*mC*A*A*G 3′;
and
(f) a nucleic acid complex comprising:
a sense strand of:
(SEQ ID NO: 676)
5′ mCUmGAmCCmUCmCUmCUmC*U*mG*U*cholesterol 3′;
and
an antisense strand of
(SEQ ID NO: 677)
5′ ACAGAGAGGAGGUCmA*mG*mC*mC*A 3′;
wherein m represents 2′-O-methyl RNA and * represents a phosphorothioate bond.
19. The method of claim 18 , wherein the nucleic acid complex is capable of penetrating the cellular membrane of the cell in the absence of a delivery vehicle.