Lipid Nanoparticles Enabling Gene Therapies: From Concepts to Clinical Utility

被引:402
作者
Kulkarni, Jayesh A. [1 ]
Cullis, Pieter R. [1 ]
van der Meel, Roy [1 ,2 ]
机构
[1] Univ British Columbia, Dept Biochem & Mol Biol, 2350 Hlth Sci Mall, Vancouver, BC V6T 1Z3, Canada
[2] Univ Med Ctr Utrecht, Dept Clin Chem & Haematol, Utrecht, Netherlands
基金
加拿大健康研究院;
关键词
gene therapy; genetic drugs; drug delivery; nucleic acid; lipid nanoparticle; ionizable cationic lipid; CATIONIC LIPIDS; MESSENGER-RNA; IMMUNOSTIMULATORY ACTIVITY; INTRACELLULAR DELIVERY; PLASMID; DNA; BIODISTRIBUTION; PARTICLES; ENCAPSULATION; LIPOSOMES;
D O I
10.1089/nat.2018.0721
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Genetic drugs based on RNA or DNA have remarkable therapeutic potential as virtually any disease can be treated by silencing a pathological gene, expressing a beneficial protein, or by editing defective genes. However, therapies based on nucleic acid polymers require sophisticated delivery systems to deliver these macromolecules to the interior of target cells. In this study, we review progress in developing nonviral lipid nanoparticle (LNP) delivery systems that have attractive properties, including ease of manufacture, reduced immune responses, multidosing capabilities, larger payloads, and flexibility of design. LNP systems represent the most advanced delivery systems for genetic drugs as it is expected that an LNP-short interfering RNA (siRNA) formulation will receive clinical approval from the Food and Drug Administration (FDA) in 2018 for treatment of the hereditary condition transthyretin-mediated amyloidosis, a fatal condition for which there is currently no treatment. This achievement is largely due to the development of optimized ionizable cationic lipids, arguably the most important factor in the clinical success of LNP-siRNA. In addition, we highlight potential LNP applications, including targeting tissues beyond the liver and therapeutic approaches based on messenger RNA or Clustered Regularly Interspaced Short Palindromic Repeats/Cas.
引用
收藏
页码:146 / 157
页数:12
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