Modified RNAi polynucleotides and uses thereof

US10633654B2 · kind B2 · utility

Assignee

• Phio Pharmaceuticals Corp. · US

Inventors

• Pamela Pavco · Longmont, US
• Joanne Kamens · Newton, US
• Tod M. Woolf · Sudbury, US
• William Salomon · Worcester, US
• Anastasia Khvorova · Boulder, US

Key dates

• Filing date: Oct 5, 2018
• Grant date: Apr 28, 2020
• Expiry date: Oct 5, 2038

Classification

• Technology area (CPC C): Chemistry; Metallurgy
• CPC primary: C12N2320/53
• WIPO field: Pharmaceuticals
• WIPO sector: Chemistry

Abstract

The invention related to improved RNAi constructs and uses thereof. The construct has a double stranded region of 19-49 nucleotides, preferably 25, 26, or 27 nucleotides, and preferable blunt-ended. The construct has selective minimal modifications to confer an optimal balance of biological activity, toxicity, stability, and target gene specificity. For example, the sense strand may be modified (e.g., one or both ends of the sense strand it/are modified by four 2′—O-mehtyl groups), such that the construct is not cleaved by Dicer or other RNAse III, and the entire length of the antisense strand is loaded into RISC. In addition, the antisense strand may also be modified by 2′—O-methyl group at the 2nd 5′-end nucleotide to greatly reduce off-target silencing. The constructs of the invention largely avoids the interferon response and sequence-independent apoptosis in mammalian cells, exhibits better serum stability, and enhance target specificity.