Lipid nanoparticle technology for therapeutic gene regulation in the liver

Dominik Witzigmann; Jayesh A Kulkarni; Jerry Leung; Sam Chen; Pieter R Cullis; Roy van der Meel

doi:10.1016/j.addr.2020.06.026

Lipid nanoparticle technology for therapeutic gene regulation in the liver

Adv Drug Deliv Rev. 2020:159:344-363. doi: 10.1016/j.addr.2020.06.026. Epub 2020 Jul 2.

Authors

Dominik Witzigmann¹, Jayesh A Kulkarni², Jerry Leung³, Sam Chen⁴, Pieter R Cullis⁵, Roy van der Meel⁶

Affiliations

¹ Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada; NanoMedicines Innovation Network (NMIN), University of British Columbia, Vancouver, BC, Canada.
² NanoMedicines Innovation Network (NMIN), University of British Columbia, Vancouver, BC, Canada; Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada; Evonik Canada, Vancouver, BC, Canada.
³ Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada.
⁴ Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada; Integrated Nanotherapeutics, Vancouver, BC, Canada.
⁵ Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada; NanoMedicines Innovation Network (NMIN), University of British Columbia, Vancouver, BC, Canada. Electronic address: pieterc@mail.ubc.ca.
⁶ Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, The Netherlands.

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).

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

Animals
Gene Expression Regulation*
Gene Transfer Techniques*
Genetic Therapy*
Humans
Lipids / administration & dosage*
Liver / metabolism*
Nanoparticles / administration & dosage*
Nanotechnology

Substances

Lipids