Nanoparticle compositions containing sugar functionalized nucleic acid carriers
Inventors
Talukder, Poulami • CHAHAL, Jasdave
Assignees
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Publication Number
US-11859201-B2
Publication Date
2024-01-02
Expiration Date
Abstract
Nanoparticle compositions for delivery of nucleic acids to subjects including carriers comprising sugar functionalized nucleic acid carriers, and therapeutic or immunogenic nucleic acid agents enclosed within the delivery molecules are described. Methods for treating or preventing diseases or conditions in a subject by administering the nanoparticle compositions that provide immune responses and synergistic therapeutic or preventive effects are provided.
Core Innovation
The disclosure relates to sugar-functionalized nucleic acid carrier nanoparticle compositions in which a carrier structure includes an amine linker (A) having proton-accepting nitrogens, a hydrophobic unit (B), and sugar moieties. The sugar moieties include a sugar moiety (Y) and a deoxy sugar moiety (Z), and the deoxy sugar moiety provides click handles such as deoxy sugar azide and deoxy-sugar thiol handles. Carrier structures are described by formulas Ia–IIb with defined combinations of A, B, and Z.
The carrier framework is used with deoxy-sugar modified dendron nanoparticle carriers, including deoxyGlucose variants and azido- and cyclodextrin-like deoxy sugar moieties. The hydrophobic unit (B) is defined as an alkyl group or an alkenyl group, including fatty-acid options and ricinoleyl/ricinoleic acid-related options, and the amine linker (A) is further defined by substituted diamines and amine-alcohol options.
The compositions are directed to improving nucleic acid delivery, tracking, and biodistribution. The nanoparticle formulation includes components such as PEG-lipids and amphipathic lipids, and nucleic acid agents include DNA and RNA, including replicon RNA (repRNA), siRNA, miRNA, sgRNA, and mRNA. The disclosure also describes immune responses, including antigen-specific immune response, in vivo SEAP mRNA expression, and characterization of nanoparticle formulation and size using dynamic light scattering (DLS).
Claims Coverage
The provided independent claims include 1, 11, and 24. Across these, the inventive coverage centers on three inventive features: a defined nucleic acid carrier architecture with A/B/Z, nanoparticle compositions that include an enclosed nucleic acid agent, and a therapeutic administration method using the nanoparticle composition for treating a disease or condition.
Nucleic acid carrier architecture with amine linker, hydrophobic unit, and deoxy sugar
A nucleic acid carrier comprising a structure wherein A is an amine linker, B is a hydrophobic unit, and Z is a deoxy sugar moiety.
Nanoparticle composition with enclosed nucleic acid agent using the A/B/Z carrier
A nanoparticle composition comprising a nucleic acid carrier and an agent enclosed therein, the nucleic acid carrier comprising a structure wherein A is an amine linker, B is a hydrophobic unit, and Z is a deoxy sugar moiety.
Therapeutic method administering A/B/Z nanoparticle composition to treat disease or condition
A method for treating a disease or condition in a subject comprising administering a therapeutically effective amount of a nanoparticle composition, where the nanoparticle composition comprises a nucleic acid carrier and an agent enclosed therein, and the nucleic acid carrier comprises a structure wherein A is an amine linker, B is a hydrophobic unit, and Z is a deoxy sugar moiety.
The independent claims jointly cover a nucleic acid carrier defined by an amine linker (A), a hydrophobic unit (B), and a deoxy sugar moiety (Z); nanoparticle compositions that enclose an agent using this carrier architecture; and therapeutic administration methods for treating a disease or condition in a subject using the nanoparticle composition.
Stated Advantages
Higher endpoint titers at weeks 3–4 for immune groups using PE Dendron_G2-2 deoxyGlucose with specific A5 vs A1/A5 variants compared against control lipid Dlin-MC3-DMA (MC3).
Higher SEAP mRNA expression in vivo with certain PEG-lipid conjugates.
Improved gene delivery.
Improved tracking and biodistribution using isotopically labeled fatty acids.
Improved nanoparticle stability and intracellular delivery.
Documented Applications
Use of deoxy-sugar modified dendron nanoparticle carriers for immunogenicity upon IM administration, evaluated using an endpoint titer assay.
In vivo SEAP mRNA expression studies using nucleic acid delivered with PEG-lipid conjugated nanoparticle formulations.
Treating or preventing disease by administering a nanoparticle composition that includes a nucleic acid carrier structure with amine linker (A), hydrophobic unit (B), and sugar/deoxy sugar moieties (Y and Z).
Nucleic acid delivery and gene-silencing/inhibiting/modifying activity using nucleic acid agents including siRNA, miRNA, sgRNA, repRNA, and mRNA.
Inducing immune responses, including an antigen-specific immune response, in connection with therapeutic or immunogenic nucleic acid agents.
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