Organic compositions to treat HSF1-related diseases
The present disclosure relates to methods of treating heat stock factor 1 (HSF1)-related diseases such as cancer, autoimmune and viral diseases, using a therapeutically effective amount of a RNAi agent to HSF.
1. A composition comprising a RNAi agent for inhibiting the expression of HSF1, the RNAi agent comprising a sense strand and an antisense strand, wherein the antisense strand comprises at least 19 contiguous nucleotides differing by 0 or 1 nucleotides from:
(i) the antisense strand sequence UUAGCAUAGAGCCUGUCUG (SEQ ID NO: 178); or
(ii) the antisense strand sequence UUUAGCAUAGAGCCUGUCU (SEQ ID NO: 179);
wherein the antisense strand comprises at least one modified backbone and/or at least one 2′-modified nucleotide, and wherein the sense strand is at least substantially complementary to the antisense strand.
2. The composition of claim 1 , wherein the composition further comprises a second RNAi agent to HSF1.
3. The composition of claim 1 , wherein the RNAi agent comprises at least one phosphorothioate linkage.
4. The composition of claim 1 , wherein the RNAi agent is ligated to one or more agent selected from: one or more diagnostic compound, reporter group, cross-linking agent, nuclease-resistance conferring moiety, natural or unusual nucleobase, lipophilic molecule, cholesterol, lipid, lectin, steroid, uvaol, hecigenin, diosgenin, terpene, triterpene, sarsasapogenin, Friedelin, epifriedelanol-derivatized lithocholic acid, vitamin, carbohydrate, dextran, pullulan, chitin, chitosan, synthetic carbohydrate, oligo lactate 15-mer, natural polymer, low- or medium-molecular weight polymer, inulin, cyclodextrin, hyaluronic acid, protein, protein-binding agent, integrin-targeting molecule, polycationic, peptide, polyamine, peptide mimic, and transferrin.
5. The composition of claim 1 , wherein the composition is a pharmaceutically effective formulation.
6. The composition of claim 2 , wherein the composition is a pharmaceutically effective formulation.
7. The composition of claim 1 , wherein all the pyrimidine nucleotides of the RNAi agent are 2′-O-methyl modified nucleotides.
8. The composition of claim 1 , wherein the antisense strand of the RNAi agent comprises:
(i) the sequence UUAGCAUAGAGCCUGUCUG (SEQ ID NO: 178); or
(ii) the sequence UUUAGCAUAGAGCCUGUCU (SEQ ID NO: 179).
9. The composition of claim 1 , wherein the sense strand of the RNAi agent comprises at least 19 contiguous nucleotides differing by 0, 1, 2, or 3 nucleotides from:
(i) the sequence CAGACAGGCUCUAUGCUAA (SEQ ID NO: 262); or
(ii) the sequence AGACAGGCUCUAUGCUAAA (SEQ ID NO: 263).
10. The composition of claim 9 , wherein the sense strand of the RNAi agent comprises at least 19 contiguous nucleotides differing by 0 or 1 nucleotides from:
(i) the sequence CAGACAGGCUCUAUGCUAA (SEQ ID NO: 262); or
(ii) the sequence AGACAGGCUCUAUGCUAAA (SEQ ID NO: 263).
11. The composition of claim 1 , wherein the RNAi agent comprises:
(i) an antisense strand that comprises the sequence UUAGCAUAGAGCCUGUCUG (SEQ ID NO: 178) and the sense strand comprises the sequence CAGACAGGCUCUAUGCUAA (SEQ ID NO: 262); or
(ii) an antisense strand that comprises the sequence UUUAGCAUAGAGCCUGUCU (SEQ ID NO: 179) and the sense strand comprises the sequence AGACAGGCUCUAUGCUAAA (SEQ ID NO: 263).
12. The composition of claim 11 , wherein the RNAi agent comprises:
(i) 2153_A22_S26 (SEQ ID Pair NOs: 346/430);
(ii) 2153_A25_S27 (SEQ ID Pair NOs: 358/442);
(iii) 2153_A81_S26 (SEQ ID Pair NOs: 370/454);
(iv) 2153_A48_S26 (SEQ ID Pair NOs: 382/466);
(v) 2153_A82_S36 (SEQ ID Pair NOs: 394/478);
(vi) 2153_A83_S36 (SEQ ID Pair NOs: 406/490); or
(vii) 2153_A84_S36 (SEQ ID Pair NOs: 418/502).
13. The composition of claim 11 , wherein the RNAi agent comprises:
(i) 2154_A22_S26 (SEQ ID Pair NOs: 347/431);
(ii) 2154_A25_S27 (SEQ ID Pair NOs: 359/443);
(iii) 2154_A81_S26 (SEQ ID Pair NOs: 371/455);
(iv) 2154_A48_S26 (SEQ ID Pair NOs: 383/467);
(v) 2154_A82_S36 (SEQ ID Pair NOs: 395/479);
(vi) 2154_A83_S36 (SEQ ID Pair NOs: 407/491); or
(vii) 2154_A84_S36 (SEQ ID Pair NOs: 419/503).