Lipids and lipid nanoparticle formulations for delivery of nucleic acids

Inventors

Ansell, Steven M. • Du, Xinyao

Assignees

Acuitas Therapeutics Inc

Abstract

Compounds are provided having the following structure: or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R1, R2, R3, L1, L2, G1, G2 and G3 are as defined herein. Use of the compounds as a component of lipid nanoparticle formulations for delivery of a therapeutic agent, compositions comprising the compounds and methods for their use and preparation are also provided.

Core Innovation

The invention relates to a compound structural class defined by a specified chemical structure and constrained substituent variables. The compounds include G1 and G2, each independently unsubstituted alkylene, G3 as unsubstituted C1-C12 alkylene, R1 and R2 as each independently C6-C24 alkyl, and R4 as C1-C12 alkyl, while R5 is H or C1-C6 alkyl.

The variable functional group R3 is selected from OR5, CN, —C(=O)OR4, —OC(=O)R4, or NR5C(=O)R4, thereby defining multiple allowed chemical variants within the scaffold. Representative compound structures are depicted as chemical drawings and MOL representations, reflecting members and variants of the claimed compound structural class.

The described cationic lipid compounds are used as components of lipid nanoparticles for delivery of nucleic acids including mRNA, antisense/siRNA, miRNA inhibitors, and plasmid DNA. The nucleic acid-lipid nanoparticle is described as providing protection from nuclease degradation in serum and improved intracellular delivery, with serum-stability and delivery modes including systemic delivery and local delivery.

Using these defined cationic (amino) lipid compounds in lipid nanoparticles achieves increased activity and improved in vivo tolerability, resulting in an enhanced therapeutic index. The nanoparticle compositions include neutral lipids, charged lipids, steroids/sterols such as cholesterol, and polymer-conjugated/PEGylated lipids, with the cationic lipid serving as a key component.

Claims Coverage

The independent claim coverage centers on one structurally defined compound with constrained substituent variables G1–G3 and R1–R5, including multiple allowed choices for R3. The dependent claims further refine the structure by additional parameter constraints and fixed substituent identities, and later dependencies extend to compositions and delivery constructs.

Overall claim coverage centers on a structurally defined compound scaffold constrained by alkylene/alkyl size ranges and by the functional-group choices for R3, with dependent claims further narrowing the scaffold and extending to compositions and delivery constructs.

Stated Advantages

Documented Applications