Delivery of RNAi therapeutics: work in progress

Abstract

RNA interference (RNAi) therapeutics appear to offer substantial opportunities for future therapy. However, post-administration RNAi effectors are typically unable to reach disease target cells in vivo without the assistance of a delivery system or vector. The main focus of this review is on lipid-based nanoparticle (LNP) delivery systems in current research and development that have at least been shown to act as effective delivery systems for functional delivery of RNAi effectors to disease target cells in vivo. The potential utility of these LNP delivery systems is growing rapidly, and LNPs are emerging as the preferred synthetic delivery systems in preclinical studies and current nonviral RNAi effector clinical trials. Moreover, studies on LNP-mediated delivery in vivo are leading to the emergence of useful biophysical parameters and physical organic chemistry rules that provide a framework for understanding in vivo delivery behaviors and outcomes. These same parameters and rules should also suggest ways and means to develop next generations of LNPs with genuine utility and long-term clinical viability.

Keywords::

• delivery systems
• lipid-based nanoparticles
• pharmacodynamics
• pharmacokinetics
• polymer-based nanoparticles
• RNA interference
• small interfering RNA
• targeting
• trafficking
• triggerability

Financial & competing interests disclosure

AD Miller is a shareholder in GlobalAcorn Ltd. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key Issues

• • RNA interference (RNAi) therapeutics are a very promising, highly selective therapeutic modality that has just arrived in early stage Phases I and II clinical trials within the last few years.

• • Latest clinical trial data appear promising, but the field remains limited by the numbers and quality of delivery systems able to mediate efficient functional delivery of RNAi effectors to target cells post administration.

• • Lipid-based nanoparticles (LNPs) are the delivery systems (vectors) with the best current preclinical and clinical performances, but there is plenty of need for improvement.

• • Fortunately, LNPs have a range of parameters that can be adapted and used to control nanoparticle biodistribution and RNAi effector pharmacokinetics. Therefore, improvements can be expected over the next 5 years of research.

• • RNAi therapeutics are probably 5–10 years from registration and routine use in clinic; however, the therapeutic potential still makes the effort worthwhile.

• • RNAi therapeutics may well represent the dominant application of nucleic acids in therapy going forward, suggesting that this will be a key to the final clinical realization of therapies that operate at the level of the gene, otherwise known as gene therapy.

Notes