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Review
. 2020:159:344-363.
doi: 10.1016/j.addr.2020.06.026. Epub 2020 Jul 2.

Lipid nanoparticle technology for therapeutic gene regulation in the liver

Dominik Witzigmann  1 , Jayesh A Kulkarni  2 , Jerry Leung  3 , Sam Chen  4 , Pieter R Cullis  5 , Roy van der Meel  6
Affiliations
Review

Lipid nanoparticle technology for therapeutic gene regulation in the liver

Dominik Witzigmann et al. Adv Drug Deliv Rev. 2020.

Abstract

Hereditary genetic disorders, cancer, and infectious diseases of the liver affect millions of people around the globe and are a major public health burden. Most contemporary treatments offer limited relief as they generally aim to alleviate disease symptoms. Targeting the root cause of diseases originating in the liver by regulating malfunctioning genes with nucleic acid-based drugs holds great promise as a therapeutic approach. However, employing nucleic acid therapeutics in vivo is challenging due to their unfavorable characteristics. Lipid nanoparticle (LNP) delivery technology is a revolutionary development that has enabled clinical translation of gene therapies. LNPs can deliver siRNA, mRNA, DNA, or gene-editing complexes, providing opportunities to treat hepatic diseases by silencing pathogenic genes, expressing therapeutic proteins, or correcting genetic defects. Here we discuss the state-of-the-art LNP technology for hepatic gene therapy including formulation design parameters, production methods, preclinical development and clinical translation.

Keywords: CRISPR/Cas9; DNA; Gene therapy; gene editing; gene expression; gene silencing; guide RNA (gRNA); hepatocyte; lipid nanoparticle (LNP); lipids; liver; messenger RNA (mRNA); small interfering RNA (siRNA).

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Figures

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Graphical abstract
Fig. 1
Fig. 1
Structure of liver lobules. The hepatic lobule is the liver’s functional unit. Blood from the portal vein and the hepatic artery traverse the lobules to the central vein. Bile canaculi transport bile from the liver to the gut. Various metabolic pathways distribute along the porto-central axis of a liver lobule. GS, glutamine synthesis; Cho, cholesterol synthesis. Liver sinusoidal endothelial cells (LSECs) line the hepatic blood vessels, while liver-resident macrophages, i.e. Kupffer cells, are localized within the hepatic sinusoids. Hepatocytes are located behind the space of Disse with a sinusoidal (basolateral) membrane towards blood circulation. Figure adapted from Mosby et al. [48]
Fig. 2
Fig. 2
Liver sinusoids. (A) Cross section of a hepatic sinusoid. Liver sinusoidal endothelial cells form clustered fenestrations also known as sieve plates [53]. Reproduced with permission. Copyright 2009 American Physiological Society (B) Distribution of sinusoidal fenestrae size in healthy humans. Average diameter of endothelial fenestrae is 107 ± 1.5 nm. Adapted from Wisse et al. [54]. (C) Kupffer cell (KC) located within the hepatic sinusoid in close proximity to endothelial cells. Adapted with permission from UCSF Office of Medical Education [55].
Fig. 3
Fig. 3
Ionizable cationic lipids or lipid-like materials (lipidoids) enabling gene therapy in the liver. Various lipid-like materials have been developed for nucleic acid delivery. The headgroups contain tertiary amines which become protonated under acidic pH and have typically no charge at neutral pH. The lipid tails contribute to making the molecule sufficiently hydrophobic to promote incorporation into LNPs while endowing either stabilizing or destabilizing properties. The above lipids are classified into three broad categories: (i) ionizable cationic lipids such as DLinDMA [133], DLin-KC2-DMA [30], and DLin-MC3-DMA [31]; (ii) lipidoids like cKK-E12 [134] and C12-200 [29]; and (iii) next- generation lipids including the biodegradable molecules L319 [130], TT3 [135], and ssPalmE [136] as well as lipids from proprietary libraries belonging to Acuitas (A9) [137] and Moderna (L5) [138].
Fig. 4
Fig. 4
Therapeutic applications of LNPs enabling genetic drug delivery. LNPs can deliver siRNA, mRNA, DNA, or gene editing complexes, providing opportunities to treat hepatic diseases by silencing pathogenic genes, expressing therapeutic proteins, or correcting genetic defects. Following LNP internalization, nucleic acid therapeutics are released into the cytoplasm. DNA vectors require nuclear translocation to be active. Adapted with permission from Buck et al. [169]. Copyright 2019 American Chemical Society.
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