Compositions and methods for delivery of RNA
Inventors
Khandhar, Amit • Reed, Steven • DUTHIE, Malcolm • Erasmus, Jesse • Carter, Darrick • BERUBE, Bryan J.
Assignees
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Publication Number
US-12133894-B2
Publication Date
2024-11-05
Expiration Date
Abstract
The disclosure provides nanoemulsion compositions and methods of making and using thereof to deliver a bioactive agent such as a nucleic acid to a subject. The nanoemulsion composition comprises a hydrophobic core based on inorganic nanoparticles in a lipid nanoparticle that allows imaging as well as delivering nucleic acids. Methods of using these particles for treatment and vaccination are also provided.
Core Innovation
The invention provides a composition comprising DNA molecules and lipid nanoparticles, where the DNA molecules comprise a sequence encoding an antigen. The lipid nanoparticles include a surface comprising cationic lipids and a hydrophobic core comprising liquid oil, and the DNA molecules are complexed to the cationic lipids to form DNA molecule-lipid nanoparticle complexes.
In the composition, the noncomplexed lipid nanoparticles are characterized as having a z-average diameter particle size measurement of about 20 nm to about 60 nm when measured using dynamic light scattering. The disclosed structure therefore couples antigen-encoding DNA with cationic lipid-containing nanoparticles having a liquid-phase oil hydrophobic core, with DNA complexing directly to the cationic lipid surface.
The disclosed embodiments further refine the lipid nanoparticle hydrophobic core by specifying liquid oil options and, where applicable, include additional structural options such as solid inorganic nanoparticles with defined average diameter ranges. The reported scope includes cationic lipid selection from specified cationic lipids and optional formulation constraints such as dry powder, together with antigen sequence and related sequence-region specifications in the DNA molecules.
Claims Coverage
The independent claim clm-00001 is directed to a composition having DNA molecules encoding an antigen complexed with cationic-lipid lipid nanoparticles having a liquid-phase oil hydrophobic core, with specified noncomplexed nanoparticle size by dynamic light scattering. The inventive features are then narrowed in dependent claims by selecting particular liquid oils and cationic lipids, specifying optional additional inorganic nanoparticle sizing constraints, and further defining DNA sequence source categories and RNA polymerase complex region sequence sources including Venezuelan equine encephalitis virus where applicable.
DNA-encoded antigen complexed with cationic lipid nanoparticles
DNA molecules comprise a sequence encoding an antigen, and the DNA molecules are complexed to cationic lipids to form DNA molecule-lipid nanoparticle complexes.
Liquid-phase oil hydrophobic core with cationic lipid surface
Lipid nanoparticles comprise a surface comprising cationic lipids and a hydrophobic core comprising liquid oil, wherein lipids present in the hydrophobic core are in liquid phase at 25 degrees Celsius.
Noncomplexed lipid nanoparticle size range by dynamic light scattering
Noncomplexed lipid nanoparticles are characterized as having a z-average diameter particle size measurement of about 20 nm to about 60 nm when measured using dynamic light scattering.
Hydrophobic liquid oil selection for the hydrophobic core
The hydrophobic core comprises a liquid oil selected from capric/caprylic triglyceride, vitamin E, lauroyl polyoxylglyceride, monoacylglycerol, squalene, or any combination thereof.
Cationic lipid selection from specified cationic lipids
The cationic lipid is selected from a specified group of cationic lipids including DOTAP, DC Cholesterol, DDA, DMTAP, DPTAP, DSTAP, DOTMA, DODAC, DOEPC, DODAP, DLinDMA, and C12-200.
Optional solid inorganic nanoparticle size constraint
The solid inorganic nanoparticle in the composition has an average diameter of about 3 nm to about 50 nm.
Dry powder formulation constraint
The composition is formulated as a dry powder.
Venezuelan equine encephalitis virus RNA polymerase complex region sequence
An RNA polymerase complex region comprises a sequence from Venezuelan equine encephalitis virus.
Overall, the claims coverage centers on forming DNA molecule-lipid nanoparticle complexes where antigen-encoding DNA is complexed to cationic lipid-containing nanoparticles with a liquid-phase oil hydrophobic core, noncomplexed nanoparticle size characterized by dynamic light scattering, and dependent claim refinements specifying particular liquid oils and cationic lipids, optional solid inorganic nanoparticle sizing, dry powder formulation, and specific sequence-region sources including Venezuelan equine encephalitis virus.
Stated Advantages
Improved RNA delivery and protection from RNases.
Stable particle/RNA complexes can be formed, including DNA/RNA complexing to cationic lipids and forming stable complexes.
MRI contrast/trackability via iron-aligned relaxivity, with enhancement of MRI relaxivity (T1/T2).
Enhanced immunogenicity, including Th1-biased antibody responses.
Documented Applications
RNA delivery and imaging, including RNA vaccines and therapeutics with antigen-encoding sequences and immune response readouts.
MRI tracking/contrast using the reported inorganic reporter component and associated relaxivity.
In vivo vaccine performance and immune response measurements in mice, rabbits, and nonhuman primates, including neutralizing antibody and PRNT80 titers.
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