Targeted inhibition using engineered oligonucleotides
Inventors
PLACE, Robert • SALEH, Anthony • WILLIAMS, Tishan
Assignees
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Publication Number
US-11597930-B2
Publication Date
2023-03-07
Expiration Date
Abstract
Disclosed herein are engineered oligonucleotides for selective inhibition of polypeptide expression and activity. Also disclosed herein are methods of selectively inhibiting polypeptide expression and activity contacting an engineered oligonucleotide with a polynucleotide encoding the polypeptide.
Core Innovation
The invention relates to engineered microRNA (miRNA) and engineered oligonucleotides configured to bind and inhibit expression or activity of polypeptides by targeting disease-associated genetic loci. The engineered miRNA or salt thereof comprises SEQ ID NO: 88, and the engineered passenger oligonucleotide or salt thereof comprises SEQ ID NO: 96 and is no more than 20 nucleotides in length. A nucleic acid construct is disclosed that comprises a first strand comprising SEQ ID NO: 88 and a second strand comprising SEQ ID NO: 96.
The engineered oligonucleotides are described in multiple forms, including antisense oligonucleotides (ASO), synthetic miRNA, and small interfering RNA (siRNA), and include engineered guide and engineered passenger oligonucleotides. Binding is further described using sequence identity thresholds to multiple SEQ IDs and by using specific oligonucleotide lengths and chemical features, including sugar/backbone/chemical modifications and linker/conjugate features for stability and targeting.
The document also describes engineered passenger/guide oligonucleotide design features, including complementarity, end overhangs, and chemical or sugar modifications. It further describes delivery vehicle options, including vectors such as viral vectors including AAV and other vector examples, and pharmaceutical compositions with pharmaceutically acceptable excipients.
Claims Coverage
The independent claim set includes three independent claims covering an engineered miRNA sequence, an engineered passenger oligonucleotide sequence with a length limitation, and a nucleic acid construct combining the two sequences as first and second strands.
Engineered microRNA comprising SEQ ID NO: 88
An engineered microRNA (miRNA) or salt thereof comprising SEQ ID NO: 88.
Engineered passenger oligonucleotide comprising SEQ ID NO: 96 and length limit
An engineered passenger oligonucleotide or salt thereof comprising SEQ ID NO: 96, wherein the engineered passenger oligonucleotide or salt thereof is no more than 20 nucleotides in length.
Nucleic acid construct with first strand SEQ ID NO: 88 and second strand SEQ ID NO: 96
A nucleic acid construct comprising a first strand comprising SEQ ID NO: 88 and a second strand comprising SEQ ID NO: 96.
Overall, claim coverage centers on the sequence-defined engineered miRNA (SEQ ID NO: 88), the corresponding short engineered passenger oligonucleotide (SEQ ID NO: 96, limited to no more than 20 nucleotides), and a nucleic acid construct that combines these two sequences as first and second strands.
Stated Advantages
Reduced immunostimulation.
Anti-tumor activity.
Antiviral activity, including SARS-CoV-2 cytoprotection.
Reduced target mRNA translation/activity.
Improved nuclease stability.
Improved RISC dependency.
Reduced polypeptide expression/activity compared to natural miR-29/miR-30 controls.
Documented Applications
Antiviral use in coronavirus contexts including SARS-CoV, SARS-CoV-2, MERS-CoV, and CoV-HKU1, and in HCV genotype 1 contexts.
Therapeutic use described as anti-tumor activity and cancer-related treatment, including subject diagnosis using a diagnostic test and cancer treatment by administering a therapeutically effective amount of the pharmaceutical composition.
Diagnostic workflow use as part of treating cancer, where the subject is diagnosed with cancer using a diagnostic test that may include imaging procedure, blood count analysis, tissue pathology analysis, biomarker analysis, or combinations of these.
Treatment of cancer in a subject using a pharmaceutical composition that includes the nucleic acid construct described in the claims.
Treatment methods for diseases including fibrosis, viral infections including SARS-CoV-2, SARS-CoV, MERS-CoV, HCV, and HIV, and muscular dystrophy, using described nucleic acid constructs, pharmaceutical compositions, and administration routes.
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