Lipids and compositions thereof

Inventors

Stanton, Matthew G. • Nolting, Birte • Milstead, Andrew

Assignees

Generation Bio Co

Abstract

Provided herein are lipids having the Formula I or Formula Ia: and pharmaceutically acceptable salts thereof, wherein R′, R1, R2, R3, R4, R5, R6a, R6b, X1, X2, and n are as defined herein for Formula I and Formula Ia, respectively. Also provided herein are lipid nanoparticle (LNP) compositions comprising lipid having the Formula I or Ia and a capsid-free, non-viral vector (e.g., ceDNA). In one aspect of any of the aspects or embodiments herein, these LNPs can be used to deliver a capsid-free, non-viral DNA vector to a target site of interest (e.g., cell, tissue, organ, and the like).

Core Innovation

The invention provides lipid nanoparticles and related cationic lipids selected by structural definitions, including lipid selected from the group of Formula I or Formula Ia and multiple sub-formula embodiments, together with pharmaceutically acceptable salts. The disclosed lipids include extended-chain ester/amido lipids and long-chain amphiphilic lipids and intermediates, with detailed synthetic examples, schemes, intermediate structures, and characterization by MS and 1H NMR.

The disclosure describes chemical synthesis of amphiphilic lipid intermediates and final cationic lipid species, including coupling with 4-(dimethylamino)butanoic acid hydrochloride or 4-(dimethylamino)butyric acid HCl, and derivatization to lipid species such as Lipid 1, Lipid 2, Lipid 11, Lipid 16, Lipid 18, Lipid 23, Lipid 24, and Lipid 25. The schemes include alkyl-substituted alcohols, aldehydes, ester/oxo/hydroxy intermediates, and amino-functionalized ester lipids, while varying ester, oxo, hydroxy, amine, methoxy(methyl)amino, and thioether/disulfide functionalities.

The disclosed cationic lipids are formulated into lipid nanoparticles containing therapeutic nucleic acid, including closed-ended DNA (ceDNA), mRNA, and siRNA, with tissue-specific targeting ligand selection and pharmaceutical compositions with excipients. The document also describes non-viral, capsid-free closed-ended linear continuous DNA vectors comprising linear covalently closed ends and a linear continuous duplex DNA, produced from expression constructs flanked by AAV inverted terminal repeats, and associated with formulation into lipid particles/lipid nanoparticles and therapeutic and diagnostic uses across genetic disorders.

The disclosure further includes formulation and in vivo preclinical study information for LNPs using these lipids with ceDNA-luciferase, including stated formulation components such as DSPC, cholesterol, DMG-PEG2000, and DSPE-PEG2000-GalNAc4. Reported study information includes encapsulation efficiency, polydispersity index, LNP diameter, luciferase expression, tolerability, and in vivo expression.

Claims Coverage

The claim coverage centers on specific lipids or lipid structural forms, with dependent claim coverage extending to lipid nanoparticles containing a therapeutic nucleic acid and to methods of treating genetic disorders. Across the claims, the inventive features include lipid selection, pharmaceutically acceptable salts, lipid nanoparticle formulation, therapeutic nucleic acid payloads, targeting ligands, non-cationic lipid selection, excipient-containing compositions, and treatment use.

Overall, the claims are directed to specific lipids, lipid nanoparticles containing therapeutic nucleic acids, and treatment of genetic disorders by administering an effective amount of such lipid nanoparticles. The dependent claims further narrow the formulation with targeting ligands, non-cationic lipid choices, pharmaceutical excipients, and enumerated genetic disorder selections.

Stated Advantages

Documented Applications