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-11648322-B2
Publication Date
2023-05-16
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 disclosure describes a composition that includes nucleic acids and lipid nanoparticles, where the lipid nanoparticles comprise a surface comprising cationic lipids and a hydrophobic core. The nucleic acids comprise a sequence encoding for an RNA polymerase complex region from an RNA virus and a SARS-CoV-2 spike protein region, and the nucleic acids are complexed to the cationic lipids to form nucleic acid-lipid nanoparticle complexes.
The composition is formulated as a dry powder. The hydrophobic core is configurable and includes inorganic reporter nanoparticles within an oil-based hydrophobic core in nanoemulsion formats, with examples including iron oxide nanoparticles and TOPO-coated inorganic cores such as aluminum oxyhydroxide. The inorganic components are used for imaging and reporting through magnetic resonance imaging contrast.
In the described examples, the nucleic acid payloads include replicon RNA and RNA-encoded antigens, and the delivery is used to support both protein expression and immune stimulation. The disclosure states that RNase protection and stability are provided, robust in vivo protein expression is achieved using an SEAP-encoding replicon RNA, and immune responses are measured, including antibody generation and Th1 bias.
Claims Coverage
Independent claim clm-00001 covers a dry-powder composition combining nucleic acids encoding an RNA virus RNA polymerase complex region and a SARS-CoV-2 spike protein region with lipid nanoparticles having a cationic-lipid surface and a hydrophobic core, where the nucleic acids are complexed to the cationic lipids to form nucleic-acid lipid nanoparticle complexes.
Dry powder nucleic-acid lipid nanoparticle complexes
The composition comprises nucleic acids complexed to cationic lipids to form nucleic acid-lipid nanoparticle complexes, and the composition is formulated as a dry powder.
Nucleic acids encoding RNA polymerase complex region and SARS-CoV-2 spike region
The nucleic acids comprise a sequence encoding an RNA polymerase complex region from an RNA virus and a SARS-CoV-2 spike protein region.
Lipid nanoparticles with cationic lipid surface and hydrophobic core
The lipid nanoparticles comprise a surface comprising cationic lipids and a hydrophobic core.
The claim coverage centers on the combination of dry-powder formulation, nucleic acids encoding an RNA virus RNA polymerase complex region plus a SARS-CoV-2 spike protein region, and lipid nanoparticles that present a cationic-lipid surface for complexing and a hydrophobic core.
Stated Advantages
Provides RNA protection from RNase challenge and supports particle stability across temperatures.
Enables robust in vivo protein expression using an SEAP-encoding replicon RNA.
Supports improved delivery and immune responses, including antibody responses and Th1 bias compared with a nanostructured lipid carrier control.
Enables MRI contrast enhancement and imaging/tracking based on iron-containing inorganic reporter nanoparticles.
Supports innate immune stimulation through delivery of RIG-I and TLR3 agonists, including induction of innate immune gene expression while protecting RNA.
Supports antibody expression and maternal transfer in rabbits.
Documented Applications
Therapeutic and vaccine use via delivery of replicon RNA and RNA-encoded antigens such as SARS-CoV-2 spike/RBD constructs.
Imaging/tracking of the formulation by magnetic resonance imaging (MRI) contrast enhancement based on inorganic reporter nanoparticles.
Innate immune stimulation use, including delivery of a RIG-I agonist and a TLR3 agonist with intranasal delivery described as dose-dependent for innate gene induction.
Administration route concepts including pulmonary/dry powder concepts and intranasal delivery.
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