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Abstract
Genetic drugs such as small interfering RNA (siRNA), mRNA, or plasmid DNA provide
potential gene therapies to treat most diseases by silencing pathological genes, expressing
therapeutic proteins, or through gene-editing applications. In order for genetic drugs
to be used clinically, however, sophisticated delivery systems are required. Lipid
nanoparticle (LNP) systems are currently the lead non-viral delivery systems for enabling
the clinical potential of genetic drugs. Application will be made to the Food and
Drug Administration (FDA) in 2017 for approval of an LNP siRNA drug to treat transthyretin-induced
amyloidosis, presently an untreatable disease. Here, we first review research leading
to the development of LNP siRNA systems capable of silencing target genes in hepatocytes
following systemic administration. Subsequently, progress made to extend LNP technology
to mRNA and plasmids for protein replacement, vaccine, and gene-editing applications
is summarized. Finally, we address current limitations of LNP technology as applied
to genetic drugs and ways in which such limitations may be overcome. It is concluded
that LNP technology, by virtue of robust and efficient formulation processes, as well
as advantages in potency, payload, and design flexibility, will be a dominant non-viral
technology to enable the enormous potential of gene therapy.