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. An RNA complex comprising an antisense strand of at least 19 nucleotides (nt) in length having sequence complementarity to an F2RL1 mRNA sequence and a sense strand of 15 to 17 nt in length having sequence complementarity to the antisense strand, wherein the antisense strand and the sense strand form a complex in which the 5′ end of the antisense strand and the 3′ end of the sense strand form a blunt end, and wherein the RNA complex has a double-stranded region of 15-17 nt in length and an overhang of at least 2 nt in length formed at the 3′ end of the antisense strand.
2. The RNA complex of claim 1 , wherein the antisense strand is 19 to 21 nt in length.
3. The RNA complex of claim 1 , wherein the antisense strand is at least 24 nt in length.
4. The RNA complex of claim 1 , wherein the sense strand comprises the sequence of SEQ ID NO: 420.
5. The RNA complex of claim 1 , wherein the antisense strand comprises the sequence of SEQ ID NO: 421.
6. The RNA complex of claim 1 , wherein the sense strand comprises the sequence of SEQ ID NO: 420 and the antisense strand comprises the sequence of SEQ ID NO: 421.
7. The RNA complex of claim 1 , wherein the RNA complex comprises a chemical modification.
8. The RNA complex of claim 7 , wherein the chemical modification is a 2′-O-methylated nucleoside, a phosphorothioate bond or a hydrophobic moiety.
9. The chemical modification of claim 8 , wherein the hydrophobic moiety is a cholesterol moiety.
10. The RNA complex of claim 7 , wherein the RNA complex comprises at least one phosphorothioate bond.
11. The RNA complex of claim 10 , wherein the RNA complex is a modified RNA complex selected from:
(a) an RNA complex consisting of:
a sense strand of: 5′ mCUmGAmCCmUCmCUmCUmC*U*mG*U*cholesterol 3′ (SEQ ID NO: 642); and
an antisense strand of: 5′ ACAGAGAGGAGGUCmAmGC*C*A*A*G 3′ (SEQ ID NO: 643);
(b) an RNA complex consisting of:
a sense strand of: 5′ mCUmGAmCCmUCmCUmCUmC*U*mG*U*cholesterol 3′ (SEQ ID NO: 644); and
an antisense strand of: 5′ ACAGAGAGGAGGUCmAmGmC*mC*A*A*G 3′ (SEQ ID NO: 645);
(c) an RNA complex consisting of:
a sense strand of: 5′ mCUmGAmCCmUCmCUmCUmC*U*mG*U*cholesterol 3′ (SEQ ID NO: 646); and
an antisense strand of 5′ ACAGAGAGGAGGUCmAmGmC*mC*mA*mA*mG 3′ (SEQ ID NO: 647);
(d) an RNA complex consisting of:
a sense strand of: 5′ mCUmGAmCCmUCmCUmCUmCU*mG*U*cholesterol 3′ (SEQ ID NO: 672); and
an antisense strand of 5′ ACAGAGAGGAGGUCmA*mG*mC*mC*A 3′ (SEQ ID NO: 673);
(e) an RNA complex consisting of:
a sense strand of: 5′ mCUmGAmCCmUCmCUmCUmCU*mG*U*cholesterol 3′ (SEQ ID NO: 674); and
an antisense strand of 5′ ACAGAGAGGAGGUCmAmGmC*mC*A*A*G 3′ (SEQ ID NO: 675); and
(f) an RNA complex consisting of:
a sense strand of: 5′ mCUmGAmCCmUCmCUmCUmC*U*mG*U*cholesterol 3′ (SEQ ID NO: 676); and
an antisense strand of 5′ ACAGAGAGGAGGUCmA*mG*mC*mC*A 3′ (SEQ ID NO: 677);
wherein m represents 2′-O-methyl RNA and * represents a phosphorothioate bond.
12. The RNA complex of claim 10 , wherein the RNA complex is capable of penetrating the cellular membrane of a cell in the absence of a delivery vehicle.
13. A pharmaceutical composition comprising an RNA complex of claim 1 and a pharmaceutically acceptable carrier.
14. The pharmaceutical composition of claim 13 , wherein the pharmaceutical composition is formulated for inhalation or for topical administration.