Nanomaterials containing constrained lipids and uses thereof
AssigneeGeorgia Tech Research Corporation
InventorsJames Everett Dahlman, Cory Dane Sago, Zubao Gan
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Abstract
Compositions for delivering nucleic acids to cells or tissue microenvironments are provided. In one embodiment, the compositions are lipid nanoparticle compositions formulated to have reduced splenic and hepatic clearance. It has been discovered that the chemical composition of lipid nanoparticles significantly influences the natural trafficking of the lipid nanoparticles. More specifically, it has been discovered that conformationally constrained ionizable lipids can modify the tropism and clearance profile of lipid nanoparticles without the need of a targeting ligand. It has also been discovered that tropism of the disclosed lipid nanoparticles is size-independent.
Claims26
A lipid nanoparticle composition comprising:
- an ionizable lipid having a structure according to
- or a pharmaceutically acceptable salt thereof;
- a phospholipid;
- a polyethylene glycol-lipid;
- a cholesterol;
- and optionally
- a nucleic acid.
A lipid nanoparticle composition comprising:
- an ionizable lipid having a structure according to
- or a pharmaceutically acceptable salt thereof;
- 1-2-distearoyl-sn-glycero-3-phosphocholine (DSPC);
- C14PEG2000;
- cholesterol;
- and
- siRNA.
A method of delivering a nucleic acid to an immune cell in a subject in need thereof, comprising:
- administering to the subject a lipid nanoparticle composition consisting of
- 3-[(1-Adamantanyl)acetoxy]-2-{[3-(diethylamino)propoxycarbonyloxy]methyl}propyl (9Z,12Z)-9,12-octadecadienoate, or a pharmaceutically acceptable salt thereof;
- DSPC;
- a polyethylene glycol-lipid;
- a cholesterol;
- and
- a nucleic acid,
- wherein the lipid nanoparticle composition delivers the nucleic acid to the immune cell in the subject.
A method for increasing delivery of a nanoparticle composition to non-hepatocyte cells in a subject comprising formulating the nanoparticle composition to comprise an amount of an ionizable lipid that is effective to increase delivery of the nanoparticle composition to non-hepatocyte cells when administered to the subject, wherein the ionizable lipid has a structure according to either
- or a pharmaceutically acceptable salt thereof.
A method for reducing gene expression in an immune cell in a subject in need thereof, comprising:
- administering to the subject a lipid nanoparticle composition consisting of
- 3-[(1-Adamantanyl)acetoxy]-2-{[3-(diethylamino)propoxycarbonyloxy]methyl}propyl (9Z,12Z)-9,12-octadecadienoate, or a pharmaceutically acceptable salt thereof;
- DSPC;
- a polyethylene glycol-lipid;
- cholesterol;
- and
- an inhibitory nucleic acid,
- wherein the lipid nanoparticle composition delivers the inhibitory nucleic acid to the immune cell in the subject.
A method for editing a gene in an immune cell in a subject in need thereof, comprising:
- administering to the subject a lipid nanoparticle composition comprising a first and second population of lipid nanoparticles,
- wherein the first population of lipid nanoparticles consists of 3-[(1-Adamantanyl)acetoxy]-2-{[3-(diethylamino)propoxycarbonyloxy]methyl}propyl (9Z,12Z)-9,12-octadecadienoate, or a pharmaceutically acceptable salt thereof, DSPC, a polyethylene glycol-lipid, cholesterol, and sgRNA specific for the gene, and
- wherein the second population of lipid nanoparticles consists of 3-[(1-Adamantanyl)acetoxy]-2-{[3-(diethylamino)propoxycarbonyloxy]methyl}propyl (9Z,12Z)-9,12-octadecadienoate, or a pharmaceutically acceptable salt thereof, DSPC, a polyethylene glycol-lipid, cholesterol, and mRNA encoding an RNA guided DNA endonuclease.
A compound having a structure that is
- or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.