Organic compositions to treat HSF1-related diseases
The present disclosure relates to methods of treating heat shock factor 1 (HSF1)-related diseases such as cancer and viral diseases, using a therapeutically effective amount of a RNAi agent to HSF.
1. A composition comprising an RNAi agent to HSF1 comprising a first strand and a second strand, wherein the sequence of the first strand comprises the nucleotide sequence of SEO ID NO: 542 (CUCACGAGGGUCCACAGCU) wherein the first and/or second strand are modified or unmodified, and wherein the first and/or second strand are no more than about 49 nt long.
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 first strand and the second strand are both about 19 to about 23 nucleotides in length.
4. The composition of claim 1 , wherein the RNAi agent comprises a modified sugar backbone, a phosphorothioate linkage, or a 2′-modified nucleotide.
5. The composition of claim 1 , wherein the RNAi agent comprises a 2′-modification selected from the group consisting of: 2′-deoxy, 2′-deoxy-2′-fluoro, 2′-O-methyl, 2′-O-methoxyethyl (2′-O-MOE), 2′-O-aminopropyl (2′-O-AP), 2′-O-dimethylaminoethyl (2′-O-DMAOE), 2′-O-dimethylaminopropyl (2′-O-DMAP), 2′-O-dimethylaminoethyloxyethyl (2′-O-DMAEOE), and 2′-O—N-methylacetamido (2′-O-NMA).
6. The composition of claim 1 , wherein the RNAi agent comprises a blunt end or an overhang having 1 to 4 unpaired nucleotides.
7. The composition of claim 1 , wherein the RNAi agent is ligated to 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, hecogenin, 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/or transferrin.
8. The composition of claim 1 , further comprising one or more additional pharmaceutical agents.
9. A composition comprising an RNAi agent to HSF1 comprising a first strand and a second strand, wherein the sequence of the first strand comprises the sequence of SEQ ID NO: 542 (CUCACGAGGGUCCACAGCU), and/or the sequence of the second strand comprises the sequence of SEQ ID NO: 30 (AGCUGUGGACCCUCGUGAG), wherein the first and/or second strand are modified or unmodified, and wherein the first and/or second strand are no more than about 49 nt long and a pharmaceutically acceptable carrier.
10. The composition of claim 9 , wherein the composition further comprises a second RNAi agent to HSF1.
11. The composition of claim 9 , wherein the first strand and the second strand are both 19 to 23 nucleotides in length.
12. The composition of claim 9 , wherein the RNAi agent comprises a modified sugar backbone, a phosphorothioate linkage, or a 2′-modified nucleotide.
13. The composition of claim 9 , wherein the RNAi agent comprises a 2′-modification selected from the group consisting of: 2′-deoxy, 2′-deoxy-2′-fluoro, 2′-O-methyl, 2′-O-methoxyethyl (2′-O-MOE), 2′-O-aminopropyl (2′-O-AP), 2′-O-dimethylaminoethyl (2′-O-DMAOE), 2′-O-dimethylaminopropyl (2′-O-DMAP), 2′-O-dimethylaminoethyloxyethyl (2′-O-DMAEOE), and 2′-O—N-methylacetamido (2′-O-NMA).
14. The composition of claim 9 , wherein the RNAi agent comprises a blunt end or an overhang having 1 to 4 unpaired nucleotides.
15. The composition of claim 9 , wherein the RNAi agent is ligated to 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, hecogenin, 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/or transferrin.
16. A method of inhibiting the expression of HSF1 in an individual, comprising the step of administering to the individual a composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of an RNAi agent to HSF1 comprising a first strand and a second strand, wherein the sequence of the first strand comprises the sequence of SEO ID NO: 542 (CUCACGAGGGUCCACAGCU), wherein the first and/or second strand are modified or unmodified, and wherein the first and/or second strand are no more than about 49 nucleotides long, the method optionally further comprising the step of administering a second RNAi agent to HSF1.
17. The method of claim 16 , wherein the individual is afflicted with an HSF1-related cancer.
18. The method of claim 17 , wherein the HSF1-related cancer is selected from the list of bladder, bone, breast, cervical, colon, colorectal, endometrial, fibrosarcoma, gastric, haematopoietic, intestine, kidney, liver, lung, lymphoma, neuroectodermal, neuroblastoma, Ewing's sarcoma, osteosarcoma, ovary, pancreas, pleura, prostate, skin, squamous cell, stomach, and testicular cancers, leukemia, promyelocytic leukemia, and Hodgkin's disease.
19. The method of claim 16 , wherein the method further comprises the step of administering one or more additional pharmaceutical agents.
20. The method of claim 16 , further comprising administering a cancer treatment.