Next-Generation Lipids in RNA Interference Therapeutics

RNA is emerging as a potential therapeutic modality for the treatment of incurable diseases. Despite intense research, the advent to clinical utility remains compromised by numerous biological barriers, hence, there is a need for sophisticated delivery vehicles. In this aspect, lipid nanoparticles (...

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Published in:	ACS nano Vol. 11; no. 8; pp. 7572 - 7586
Main Authors:	Rietwyk, Stephanie, Peer, Dan
Format:	Journal Article
Language:	English
Published:	United States American Chemical Society 22.08.2017
Subjects:	Animals Cations - chemistry Gene Silencing - physiology Humans Lipids - chemistry Nanoparticles - chemistry RNA Interference - physiology RNA, Small Interfering - genetics RNA, Small Interfering - physiology toxicity RNAi therapeutics lipidoids delivery lipid nanoparticles RNA interference cationic lipids ionizable amino lipids gene silencing siRNA
ISSN:	1936-0851, 1936-086X, 1936-086X
Online Access:	Get full text
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Abstract	RNA is emerging as a potential therapeutic modality for the treatment of incurable diseases. Despite intense research, the advent to clinical utility remains compromised by numerous biological barriers, hence, there is a need for sophisticated delivery vehicles. In this aspect, lipid nanoparticles (LNPs) are the most advanced platform among nonviral vectors for gene delivery. In this review, we critically review the literature and the reasons for ineffective delivery beyond the liver. We discuss the toxicity issues associated with permanently charged cationic lipids and then turn our attention to next-generation ionizable cationic lipids. These lipids exhibit reduced toxicity and immunogenicity and undergo ionization under the acidic environment of the endosome to release the encapsulated payload to their site of action in the cytosol. Finally, we summarize recent achievements in therapeutic nucleic acid delivery and report on the current status of clinical trials using LNP and the obstacles to clinical translation.
AbstractList	RNA is emerging as a potential therapeutic modality for the treatment of incurable diseases. Despite intense research, the advent to clinical utility remains compromised by numerous biological barriers, hence, there is a need for sophisticated delivery vehicles. In this aspect, lipid nanoparticles (LNPs) are the most advanced platform among nonviral vectors for gene delivery. In this review, we critically review the literature and the reasons for ineffective delivery beyond the liver. We discuss the toxicity issues associated with permanently charged cationic lipids and then turn our attention to next-generation ionizable cationic lipids. These lipids exhibit reduced toxicity and immunogenicity and undergo ionization under the acidic environment of the endosome to release the encapsulated payload to their site of action in the cytosol. Finally, we summarize recent achievements in therapeutic nucleic acid delivery and report on the current status of clinical trials using LNP and the obstacles to clinical translation. RNA is emerging as a potential therapeutic modality for the treatment of incurable diseases. Despite intense research, the advent to clinical utility remains compromised by numerous biological barriers, hence, there is a need for sophisticated delivery vehicles. In this aspect, lipid nanoparticles (LNPs) are the most advanced platform among nonviral vectors for gene delivery. In this review, we critically review the literature and the reasons for ineffective delivery beyond the liver. We discuss the toxicity issues associated with permanently charged cationic lipids and then turn our attention to next-generation ionizable cationic lipids. These lipids exhibit reduced toxicity and immunogenicity and undergo ionization under the acidic environment of the endosome to release the encapsulated payload to their site of action in the cytosol. Finally, we summarize recent achievements in therapeutic nucleic acid delivery and report on the current status of clinical trials using LNP and the obstacles to clinical translation.RNA is emerging as a potential therapeutic modality for the treatment of incurable diseases. Despite intense research, the advent to clinical utility remains compromised by numerous biological barriers, hence, there is a need for sophisticated delivery vehicles. In this aspect, lipid nanoparticles (LNPs) are the most advanced platform among nonviral vectors for gene delivery. In this review, we critically review the literature and the reasons for ineffective delivery beyond the liver. We discuss the toxicity issues associated with permanently charged cationic lipids and then turn our attention to next-generation ionizable cationic lipids. These lipids exhibit reduced toxicity and immunogenicity and undergo ionization under the acidic environment of the endosome to release the encapsulated payload to their site of action in the cytosol. Finally, we summarize recent achievements in therapeutic nucleic acid delivery and report on the current status of clinical trials using LNP and the obstacles to clinical translation.
Author	Rietwyk, Stephanie Peer, Dan
AuthorAffiliation	Laboratory of Precision NanoMedicine, Department of Cell Research & Immunology, George S. Wise Faculty of Life Sciences Cancer Biology Research Center Tel Aviv University Department of Materials Sciences and Engineering, Iby and Aladar Fleischman Faculty of Engineering Center for Nanoscience and Nanotechnology
AuthorAffiliation_xml	– name: Laboratory of Precision NanoMedicine, Department of Cell Research & Immunology, George S. Wise Faculty of Life Sciences – name: Department of Materials Sciences and Engineering, Iby and Aladar Fleischman Faculty of Engineering – name: Center for Nanoscience and Nanotechnology – name: Tel Aviv University – name: Cancer Biology Research Center
Author_xml	– sequence: 1 givenname: Stephanie surname: Rietwyk fullname: Rietwyk, Stephanie – sequence: 2 givenname: Dan orcidid: 0000-0003-4408-8350 surname: Peer fullname: Peer, Dan email: peer@tauex.tau.ac.il
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/28727419$$D View this record in MEDLINE/PubMed
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Snippet	RNA is emerging as a potential therapeutic modality for the treatment of incurable diseases. Despite intense research, the advent to clinical utility remains...
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SubjectTerms	Animals Cations - chemistry Gene Silencing - physiology Humans Lipids - chemistry Nanoparticles - chemistry RNA Interference - physiology RNA, Small Interfering - genetics RNA, Small Interfering - physiology
Title	Next-Generation Lipids in RNA Interference Therapeutics
URI	http://dx.doi.org/10.1021/acsnano.7b04734 https://www.ncbi.nlm.nih.gov/pubmed/28727419 https://www.proquest.com/docview/1922503971
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