Organic compositions to treat HSF1-related diseases

A technology of composition and disease, applied in the field of RNAi agent, human subject in pathological state, able to solve the problem of inactivity

Inactive Publication Date: 2014-07-16
ARROWHEAD RES CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In humans and other vertebrates, HSF1 is constitutively produced at non-shock temperatures, but is inactive and bound by the protein HSP90

Method used

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  • Organic compositions to treat HSF1-related diseases
  • Organic compositions to treat HSF1-related diseases
  • Organic compositions to treat HSF1-related diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0140] Several specific specific embodiments of the disclosure herein are described below.

[0141] In one embodiment, the disclosure herein relates to a composition according to any of the foregoing embodiments for use in a method of treating HSF1-related diseases in an individual, the method comprising administering to the individual a therapeutically effective amount of Of the composition.

[0142] Several specific specific embodiments of this embodiment are described below.

[0143] In one embodiment, the disclosure herein relates to a composition according to any of the above embodiments for use in a method of inhibiting HSF1 expression in an individual, the method comprising administering to the individual a therapeutically effective amount of according to any of the above embodiments Of the composition.

[0144] One embodiment of the disclosure herein is the use of the composition according to any of the above embodiments in the preparation of a medicament for the treatment of...

Embodiment 1

[0929] Example 1. Sequence of RNAi agent against HSF1

[0930] Table A1 above provides a list linking the names of RNAi agents against HSF1 to the target sequence SEQ ID NO, as well as unmodified and modified variants. The actual sequence is provided below.

[0931] Table 1 provides the sequence of the target sequence (sense and antisense).

[0932] Table 2 provides exemplary unmodified variants (sense and antisense) of RNAi agents against HSF1.

[0933] Table 3 provides exemplary modified variants (sense and antisense) of RNAi agents against HSF1. Seven different chemical modifications are presented to multiple nucleotide duplex sequences. For each of them, the prefix of the duplex name indicates the position (nt) of the HSF1 transcript. Therefore, hs_HSF1_562_ starts at nt562 of the HSF1 transcript. Therefore, all RNAi agents with the same prefix (for example, hs_HSF1_562_) have the same nucleotide sequence despite the difference in chemical modification. The suffix (for exampl...

Embodiment 1A

[0934] Example 1A. HSF1 RNAi agent sequence and target sequence

[0935] Table 1. HSF1 RNAi agent target sequence

[0936] Provide the name of the HSF1 RNAi agent, as well as the antisense sequence (AS) and sense sequence (S) against the target sequence (each sequence name starts with hs_HSF1_*, where * is the name provided in each line; for example, "175_A22_S26" Same as "hs_HSF1_175_A22_S26", etc.). Note that the target sequence is presented as DNA (with DNA nucleotides and T instead of U). The corresponding RNAi agent will contain the corresponding RNA sequence (with RNA nucleotides and U instead of T). The RNAi agent may optionally further include terminal UU or TT on either or both strands, and may include modifications, as shown in the modification example group below.

[0937] In various embodiments, it refers to "RNAi agent (having) Table 1 (sequence)", "RNAi agent comprising a first strand and a second strand, wherein the sequence of the first strand includes (or) the seq...

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Abstract

The present disclosure relates to methods of treating heat shock factor 1 (HSF1)-related diseases such as cancer, autoimmune and viral diseases, using a therapeutically effective amount of a RNAi agent to HSF.

Description

Background of the invention [0001] HSF1 is the main regulator of the heat shock response in which multiple genes are induced in response to temperature rise and other stresses. In humans and other vertebrates, HSF1 is constitutively produced at non-shock temperatures, but is inactive and bound by the protein HSP90. At elevated temperatures, HSF1 is released by HSP90, moves from the cytoplasm to the nucleus, and trimers. The active HSF1 binds to the heat shock element (HSE) in DNA and activates the transcription of heat shock genes by RNA polymerase II. HSE has a consensus sequence of three NGAAN repeats and is present in the promoter regions of HSP90, HSP70 and HSP27 genes. During the 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 in Chu et al. 1996 J. Biol. Chem. 271: 30847-30857; Huang et al. 1997 J. Biol. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/113A61P35/00A61P31/12A61P37/06
CPCC12N2310/14C12N15/113A61K31/5377A61K31/713C12N2320/31A61P31/12A61P35/00A61P35/02A61P37/02A61P37/06A61P43/00C12N2310/321C12N2310/3521C12N2310/322C12N2310/3525A61K45/06C12N2310/333C12N2310/334C12N2310/335C12N2310/336C12N2310/351
Inventor 陈锦云K·甘姆帕D·许斯肯F·P·斯泰格迈尔M·斯塔普C·瓦热塞J·魏勒W·周
Owner ARROWHEAD RES CORP
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