RNA interference compositions targeting heat shock protein 90 and methods of use thereof
Inventors
Shemi, Amotz • ZORDE KHVALEVSKY, Elina
Assignees
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Publication Number
US-10006030-B2
Publication Date
2018-06-26
Expiration Date
Abstract
This disclosure relates to RNA interference (RNAi) compositions that target expression of heat shock protein 90 (HSP90) in a subject. Polymeric delivery devices for providing the RNAi compositions are also described, as are methods of treating cancer using the described RNAi compositions.
Core Innovation
The invention relates to RNA interference (RNAi) agents for treating a patient having a cancer in which cells of the cancer are expressing heat shock protein 90 (HSP90). The RNAi agent comprises a double-stranded RNA molecule that targets an HSP90 sequence set forth as SEQ ID NO: 1 or targets an HSP90 sequence set forth as SEQ ID NO: 2. The RNAi agent that targets SEQ ID NO: 1 comprises a sense strand of SEQ ID NO: 4 and an antisense strand of SEQ ID NO: 8, and the RNAi agent that targets SEQ ID NO: 2 comprises a sense strand of SEQ ID NO: 5 and an antisense strand of SEQ ID NO: 9.
The disclosure further supports strand and terminus designs and optional nucleotide, backbone, and sugar modifications for the double-stranded RNA molecule, including 2′-O-methyl, 2′-fluoro, locked nucleic acid (LNA), phosphorothioate, and dTdT 3′ overhangs. It also describes biodegradable polymeric drug delivery devices incorporating the RNAi agents, with polymeric matrices including PLGA, PLA, and PGA, and additives and pH-modulating additives such as mannitol, trehalose, and sodium bicarbonate.
Treatment is described for HSP90-expressing cancers, including solid tumors via implantation into the tumor or tumor bed. The document also reports functional results showing that HSP90-targeting siRNA decreases prostate cancer cell viability and decreases AR-reporter activity, and that delivery by the biodegradable polymeric device induces tumor necrosis with reduced dividing cells as shown in the provided figures.
Claims Coverage
The independent claim covers an RNAi (double-stranded RNA) agent for treating a patient with HSP90-expressing cancer. The coverage includes two targeting variants defined by SEQ ID NO: 1 and SEQ ID NO: 2, and their corresponding sense/antisense strand assignments (SEQ ID NOs: 4/8 or 5/9). Dependent claim coverage further refines nucleic-acid strand chemical modifications and adds conjugation and treatment administering limitations.
HSP90-targeting double-stranded RNA agent for cancer treatment
An RNAi agent comprising a double-stranded RNA molecule that targets a HSP90 sequence set forth as SEQ ID NO: 1 or a double-stranded RNA molecule that targets a HSP90 sequence set forth as SEQ ID NO: 2 for treating a patient having a cancer in which the cancer cells express HSP90.
Defined sense/antisense strand assignments for SEQ ID NO: 1 targeting
For the RNAi agent targeting SEQ ID NO: 1, the agent comprises a sense strand of SEQ ID NO: 4 and an antisense strand of SEQ ID NO: 8.
Defined sense/antisense strand assignments for SEQ ID NO: 2 targeting
For the RNAi agent targeting SEQ ID NO: 2, the agent comprises a sense strand of SEQ ID NO: 5 and an antisense strand of SEQ ID NO: 9.
Nucleic-acid strand chemical modification of at least one strand
At least one of the sense strand or the antisense strand is modified with one or more selected nucleic-acid modifications from a defined group including 2′-O-methyl, 2′-O-(2-methoxyethyl), 2′-F, LNA, and phosphorothioate.
2′-O-methyl sense strand pairing including SEQ ID NO: 7
The sense strand targeting SEQ ID NO: 1 is 2′-O-methyl-modified and includes the sequence set forth as SEQ ID NO: 7.
Conjugated RNAi agent with moiety or ligand
The RNAi agent is conjugated to a cholesterol, an α-tocopherol moiety, or a cell-penetrating peptide.
Method of treating an HSP90-expressing cancer by administering the RNAi agent
A method of treating a subject’s cancer that expresses HSP90 by administering the RNAi agent.
Overall, the claims cover HSP90-targeting double-stranded RNA agents defined by specific HSP90 target sequences (SEQ ID NO: 1 or SEQ ID NO: 2) with corresponding defined sense/antisense strand assignments, optionally incorporating nucleic-acid strand chemical modifications, optionally using a specific 2′-O-methyl variant for the SEQ ID NO: 1 case, optionally forming conjugates, and optionally implementing treatment by administering the RNAi agent.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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