Organic compositions to treat HSF1-related diseases

Inventors

Hinkle, Gregory • KUCHIMANCHI, Satyanarayana • Milstein, Stuart • Warmuth, Markus • Zhou, Wenlai • Zhu, Ping • ZIMMERMANN, Tracy S.

Assignees

Arrowhead Pharmaceuticals Inc

Abstract

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.

Core Innovation

The disclosure describes RNA interference (RNAi) agents targeting heat shock factor 1 (HSF1) for treating HSF1-related diseases. The RNAi agent comprises a first strand and a second strand, where the first strand includes the nucleotide sequence of SEQ ID NO: 542 (CUCACGAGGGUCCACAGCU), and the strands may be modified or unmodified and no more than about 49 nt long.

In some embodiments, the RNAi agent includes a second strand comprising SEQ ID NO: 30 (AGCUGUGGACCCUCGUGAG), and the compositions may be formulated with a pharmaceutically acceptable carrier. The disclosure further specifies RNA chemistry and structural end features, including a modified sugar backbone, phosphorothioate linkages, 2′-modified nucleotides, blunt ends, or overhangs containing 1 to 4 unpaired nucleotides.

The document additionally describes options for ligating the RNAi agent to one or more moieties, including diagnostic compounds, reporter groups, binding/targeting ligands, and other chemical moieties such as lipophilic and lipid components. The disclosed use cases include cancer, viral diseases, and autoimmune diseases, and the compositions are described in connection with HSF1 biology and heat shock response pathways associated with proteins such as HSP90, HSP70, and HSP27.

Claims Coverage

The independent claims cover three related inventive categories: HSF1-targeting RNAi agent compositions with a specified sequence constraint, pharmaceutical compositions including a pharmaceutically acceptable carrier, and methods of inhibiting HSF1 expression in an individual using the specified RNAi agent, optionally with a second HSF1-targeting RNAi agent. The main inventive features total four core themes.

Across the independent claims, the coverage centers on HSF1-targeting RNAi agents that include the specific SEQ ID NO: 542 sequence in a defined strand-length limit of no more than about 49 nt, with strand modification being optional, and optionally incorporating a second HSF1-targeting RNAi agent. Additional coverage is provided for a pharmaceutical composition including a pharmaceutically acceptable carrier and, in one independent claim, the inclusion of SEQ ID NO: 30 in the second strand.

Stated Advantages

Documented Applications