Engineered nucleic acids and methods of use thereof
Inventors
Bancel, Stephane • Schrum, Jason P. • Aristarkhov, Alexander
Assignees
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Publication Number
US-9464124-B2
Publication Date
2016-10-11
Expiration Date
Abstract
Provided are compositions and methods for delivering biological moieties such as modified nucleic acids into cells to kill or reduce the growth of microorganisms. Such compositions and methods include the use of modified messenger RNAs, and are useful to treat or prevent microbial infection, or to improve a subject's heath or wellbeing.
Core Innovation
The patent describes engineered modified nucleic acids comprising synthetic messenger ribonucleic acid (mRNA) encoding a defensin polypeptide, formulated as a lipid-based nanoparticle or packaged in a kit. The synthetic mRNA comprises a translatable region containing at least one nucleoside modification, and 75-100% of uridine nucleotides in the synthetic mRNA are modified.
The nucleoside modifications reduce innate immune activation and nucleic acid degradation while increasing intracellular translation and cell viability. The document associates these effects with innate immune response pathways, including interferon (Type I) and TLR7/TLR8 contexts, and in some embodiments the mRNA includes a 5′ untranslated region and a 3′ untranslated region with nucleoside modifications present in each region.
The patent further describes defensin polypeptides including α-defensins, β-defensins, and θ-defensins, with examples including hBD-2, LL-37, and RNase-7. It frames the approach as a therapeutic strategy for microbial infections and also references broader cancer-related contexts, including combinations of multiple antimicrobial polypeptides or an antimicrobial polypeptide with an antibiotic to address resistance.
Claims Coverage
The independent claims cover three core categories: a lipid-based nanoparticle pharmaceutical composition, a kit, and a lipid-based nanoparticle with nucleoside modifications distributed across the translatable region, 5′ untranslated region, and 3′ untranslated region. Across these claims, the shared inventive requirements include encoding a defensin polypeptide, using a translatable region with at least one nucleoside modification, and specifying that 75-100% of uridine nucleotides are modified.
Lipid-based nanoparticle delivering synthetic defensin-encoding mRNA with high uridine modification
A lipid-based nanoparticle comprising a synthetic messenger ribonucleic acid (mRNA) encoding a defensin polypeptide in an amount effective to permit production of the defensin polypeptide in a cell, wherein the synthetic mRNA comprises a translatable region that contains at least one nucleoside modification, and wherein 75-100% of uridine nucleotides in the synthetic mRNA are modified.
Kit with synthetic defensin-encoding mRNA and pharmaceutically acceptable carrier
A kit comprising a synthetic messenger ribonucleic acid (mRNA) encoding a defensin polypeptide packaged in a container, wherein the synthetic mRNA comprises a translatable region that contains at least one nucleoside modification, and wherein 75-100% of uridine nucleotides in the synthetic mRNA are modified, and a pharmaceutically acceptable carrier packaged in a container.
Lipid-based nanoparticle with nucleoside modifications in translatable region and both UTRs
A lipid-based nanoparticle comprising a synthetic messenger ribonucleic acid (mRNA) encoding a defensin polypeptide in an amount effective to permit production of the defensin polypeptide in a cell, wherein 75-100% of uridine nucleotides in the synthetic mRNA are modified, and wherein the synthetic mRNA comprises a translatable region, a 5′ untranslated region and a 3′ untranslated region, each of which contains at least one nucleoside modification.
Collectively, the independent claims define modified synthetic mRNA that encodes a defensin polypeptide and is associated with a lipid-based nanoparticle and/or a kit format. The claims require that the translatable region contains at least one nucleoside modification and that 75-100% of uridine nucleotides are modified, with a further distribution requirement across the translatable region and both untranslated regions in one independent claim.
Stated Advantages
Reduce innate immune activation.
Reduce nucleic acid degradation.
Increase intracellular translation.
Increase cell viability.
Documented Applications
Therapeutic use against microbial infections, including bacterial, viral, fungal, protozoal, parasitic, and prion infections.
Therapeutic use in cancer-related contexts.
Use in expression frameworks for producing antimicrobial polypeptides in human/animal cells.
Use involving combinations of multiple antimicrobial polypeptides or an antimicrobial polypeptide plus an antibiotic to mitigate resistance.
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