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AssigneeArrowhead Pharmaceuticals, Inc.
InventorsGregory Hinkle, Satyanarayana Kuchimanchi, Stuart Milstein, Markus Warmuth, Wenlai Zhou, Ping Zhu, Tracy S. Zimmermann
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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.
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:633, SEQ ID NO:634, or SEQ ID NO:636, 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.
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:633, SEQ ID NO:634, or SEQ ID NO:636, 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.
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 SEQ ID NO:633, SEQ ID NO:634, or SEQ ID NO:636, 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.
Dependencies are inferred from the claim text.
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DNA or RNA fragments; Modified forms thereof ; Non-coding nucleic acids having a biological activity: non-coding nucleic acids modulating the…
Compounds having three or more nucleosides or nucleotides: double-stranded nucleic acids or oligonucleotides
Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00: mixtures of active ingredients without…
Drugs for skeletal disorders: for joint disorders, e.g. arthritis, arthrosis
About 4 years 2 months of term left · ends 16 Dec 2030 (estimated)
HSF1 is the master regulator of the heat shock response, in which multiple genes are induced in response to temperature increase and other stresses. At non-shock temperatures in humans and other vertebrates, HSF1 is produced constitutively, but is inactive and bound by protein HSP90. At an elevated temperature, HSF1 is released by HSP90, moves from the cytoplasm to the nucleus, and trimerizes. This active HSF1 binds to heat shock elements (HSE) in DNA and activates transcription of heat shock genes by RNA polymerase II. The HSE has a consensus sequence of three repeats of NGAAN and is present in the promoter regions of the HSP90, HSP70 and HSP27 genes. During cessation of the heat shock response, HSF1 is phosphorylated by mitogen-activated protein kinases (MAPKs) and glycogen synthase kinase 3 (GSK3) and returns to an inactive state. The biochemistry of HSF1 is described, inter alia, in Chu et al. 1996 J. Biol. Chem. 271:30847-30857; Huang et al. 1997 J. Biol. Chem. 272:26009-26016; and Morimoto et al. 1998 Nat. Biotech. 16: 833-838.
HSF1 interacts with additional factors. HSF1 binds to DNA-dependent protein kinase (DNA-PK), which is involved in DNA repair. HSF1 is a target of mitogen-activated protein kinases, and its activity is down-regulated when the RAS signaling cascade is active.
Additional heat shock factor proteins in humans include HSF2, HSF3, and HSF4. HSF1, HSF2, and HSF3 are positive regulators of heat shock gene expression, while HSF4 is a negative regulator. HSF1, HSF2 and HSF4 play a role in transcriptional control of other heat shock proteins. The various HSF proteins share about 40% sequence identity.
FIG. 1 illustrates various 5′-end modifications of RNAi agents to HSF1.
The present disclosure encompasses RNAi agents to HSF1, useful in treatment of HSF1-related disease, such as cancer and viral diseases.
The present disclosure provides RNAi agents directed to the HSF1 (heat shock factor 1) gene. HSF1 is the master regulator of the heat shock response, in which multiple genes are induced in response to temperature increase and other stresses.
HSF1 has been implicated in several HSF1-related diseases, including cancer and viral diseases. HSF1 and other heat shock proteins (whose expression is increased by HSF1) are over-expressed in, or have otherwise been implicated in breast, endometrial, fibrosarcoma, gastric, kidney, liver, lung, lymphoma, neuroectodermal, neuroblastoma, Ewing's sarcoma, prostate, skin, squamous cell, and testicular cancers, leukemia (e.g., promyelocytic leukemia), and Hodgkin's disease.