1 Department of Biochemistry and Molecular Biology, University of British Columbia , Vancouver, British Columbia, Canada .
2 Department of Clinical Chemistry and Haematology, University Medical Center Utrecht , Utrecht, the Netherlands .
Nucleic Acid Ther. 2018 Jun;28(3):146-157. doi: 10.1089/nat.2018.0721. Epub 2018 Apr 23.
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.
基于 RNA 或 DNA 的基因药物具有显著的治疗潜力，因为几乎任何疾病都可以通过沉默病理性基因、表达有益蛋白或编辑缺陷基因来治疗。然而，基于核酸聚合物的疗法需要复杂的递药系统将这些大分子递送到靶细胞内部。在本研究中，我们综述了开发非病毒脂质纳米颗粒（LNP）递药系统的进展，这些系统具有吸引人的特性，包括易于制造、减少免疫反应、多次给药能力、更大的载药量和设计的灵活性。LNP 系统是基因药物最先进的递药系统，预计在 2018 年，一种 LNP-小干扰 RNA（siRNA）制剂将获得美国食品和药物管理局（FDA）的临床批准，用于治疗遗传性转甲状腺素介导淀粉样变性，这是一种致命疾病，目前尚无治疗方法。这一成就主要归功于优化的可离子化阳离子脂质的开发，这可以说是 LNP-siRNA 临床成功的最重要因素。此外，我们还强调了 LNP 的潜在应用，包括靶向肝脏以外的组织和基于信使 RNA 或簇状规则间隔短回文重复序列/ Cas 的治疗方法。
