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Curated Papers > High-impact authoritative literature on "CRISPR gene editing"

Lipid-Nanoparticle-Based Delivery of CRISPR/Cas9 Genome-Editing Components. ​

Literature Information ​

DOI10.1021/acs.molpharmaceut.1c00916
PMID35594500
JournalMolecular pharmaceutics
Impact Factor4.5
JCR QuartileQ1
Publication Year2022
Times Cited82
KeywordsCRISPR/Cas9, gene therapy, genome editing, lipid nanoparticles, nanomedicine
Literature TypeJournal Article, Review, Research Support, Non-U.S. Gov't
ISSN1543-8384
Pages1669-1686
Issue19(6)
AuthorsPardis Kazemian, Si-Yue Yu, Sarah B Thomson, Alexandra Birkenshaw, Blair R Leavitt, Colin J D Ross

TL;DR ​

This review highlights the potential of CRISPR/Cas9 gene editing as a therapeutic approach for genetic diseases and cancers, emphasizing the challenges in delivering its components safely and effectively. It focuses on lipid nanoparticles (LNPs) as a promising nonviral delivery system, discussing their advantages, recent advancements, and future considerations for clinical applications in CRISPR-mediated gene therapy.

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CRISPR/Cas9 · gene therapy · genome editing · lipid nanoparticles · nanomedicine

Abstract ​

Gene editing mediated by CRISPR/Cas9 systems is due to become a beneficial therapeutic option for treating genetic diseases and some cancers. However, there are challenges in delivering CRISPR components which necessitate sophisticated delivery systems for safe and effective genome editing. Lipid nanoparticles (LNPs) have become an attractive nonviral delivery platform for CRISPR-mediated genome editing due to their low immunogenicity and application flexibility. In this review, we provide a background of CRISPR-mediated gene therapy, as well as LNPs and their applicable characteristics for delivering CRISPR components. We then highlight the challenges of CRISPR delivery, which have driven the significant development of new, safe, and optimized LNP formulations in the past decade. Finally, we discuss considerations for using LNPs to deliver CRISPR and future perspectives on clinical translation of LNP-CRISPR gene editing.

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Primary Questions Addressed ​

  1. What are the specific advantages of using lipid nanoparticles over other delivery systems for CRISPR components?
  2. How do lipid nanoparticles enhance the stability and bioavailability of CRISPR/Cas9 components in vivo?
  3. What are the current limitations and challenges faced in the clinical application of lipid nanoparticle-based CRISPR delivery systems?
  4. How might future advancements in lipid nanoparticle technology impact the efficacy of CRISPR gene editing therapies?
  5. What are the regulatory considerations for the use of lipid nanoparticles in delivering CRISPR/Cas9 components for therapeutic purposes?

Key Findings ​

Research Background and Purpose ​

The review discusses the delivery of CRISPR/Cas9 genome-editing components using lipid nanoparticles (LNPs). CRISPR technology has emerged as a powerful tool for gene therapy, offering potential treatments for genetic disorders and certain cancers. However, effective delivery of CRISPR components remains a significant challenge due to issues related to immunogenicity, stability, and cellular uptake. The review aims to highlight the advancements in LNP formulations as non-viral delivery systems that can enhance the efficacy and safety of CRISPR/Cas9 applications.

Main Methods/Materials/Experimental Design ​

The review employs a comprehensive analysis of existing literature to explore the development and optimization of LNPs for CRISPR delivery. Key aspects include:

  • LNP Composition: LNPs typically consist of ionizable cationic lipids, PEG lipids, zwitterionic phospholipids, and cholesterol. These components are critical for encapsulation, stability, and cellular uptake.
  • Encapsulation Techniques: Various formulations are explored, including:
    • Plasmid DNA (pDNA) encoding Cas9 and gRNA.
    • mRNA for Cas9 and gRNA.
    • Ribonucleoprotein (RNP) complexes of Cas9 protein and gRNA.

The following flowchart illustrates the delivery process:

Mermaid diagram

Key Results and Findings ​

  1. Delivery Efficiency: LNPs have shown superior performance in encapsulating and delivering CRISPR components compared to traditional viral vectors. They exhibit lower immunogenicity and can effectively deliver larger nucleic acid payloads.
  2. Clinical Translation: The review highlights the successful application of LNPs in clinical trials, such as ONPATTRO for hereditary transthyretin amyloidosis and ongoing trials for CRISPR/Cas9 therapies targeting genetic disorders.
  3. Targeting Specificity: The inherent properties of LNPs allow for selective targeting of liver tissues, which is beneficial for therapies aimed at liver-related genetic diseases. Modifications to LNP formulations have also enabled targeting of extrahepatic tissues.

Main Conclusions/Significance/Innovation ​

The review concludes that LNPs represent a promising non-viral delivery platform for CRISPR/Cas9 gene editing, overcoming many of the challenges associated with nucleic acid delivery. Their versatility allows for customization to enhance delivery efficiency, target specificity, and safety, paving the way for the clinical application of gene editing technologies.

Research Limitations and Future Directions ​

  • Limitations: The review acknowledges that while LNPs improve delivery efficiency, challenges such as potential off-target effects and the need for precise dosing regimens remain. The long-term safety of repeated LNP administrations is also a concern.
  • Future Directions: Future research should focus on optimizing LNP formulations for specific tissue targeting, developing strategies to minimize off-target effects, and enhancing the delivery of donor DNA templates for homology-directed repair (HDR) applications.

Summary Table of Key Components in LNP Formulations ​

ComponentFunction
Ionizable Cationic LipidsEnhance encapsulation and facilitate cellular uptake
PEG LipidsImprove stability and circulation time
Zwitterionic PhospholipidsStabilize the LNP structure
CholesterolIncrease particle stability and promote membrane fusion

This structured summary encapsulates the essential aspects of the review, providing a comprehensive overview of the advancements in LNP-based delivery systems for CRISPR/Cas9 genome editing.

References ​

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Literatures Citing This Work ​

  1. The promise of gene editing: so close and yet so perilously far. - David J Segal - Frontiers in genome editing (2022)
  2. Nanocarriers: A novel strategy for the delivery of CRISPR/Cas systems. - Faranak Hejabi;Mohammad Sadegh Abbaszadeh;Shirinsadat Taji;Andrew O'Neill;Fatemeh Farjadian;Mohammad Doroudian - Frontiers in chemistry (2022)
  3. Delivery of RNAs to Specific Organs by Lipid Nanoparticles for Gene Therapy. - Kelly Godbout;Jacques P Tremblay - Pharmaceutics (2022)
  4. In vivo delivery of CRISPR-Cas9 genome editing components for therapeutic applications. - Kun Huang;Daniel Zapata;Yan Tang;Yong Teng;Yamin Li - Biomaterials (2022)
  5. Lipid-mRNA nanoparticles landscape for cancer therapy. - Yin Li;Hengtong Fang;Tao Zhang;Yu Wang;Tingting Qi;Bai Li;Huping Jiao - Frontiers in bioengineering and biotechnology (2022)
  6. Advanced Nanomedicine for High-Risk HPV-Driven Head and Neck Cancer. - Qiang Xu;Ye Chen;Yuan Jin;Zhiyu Wang;Haoru Dong;Andreas M Kaufmann;Andreas E Albers;Xu Qian - Viruses (2022)
  7. Shaping the future from the small scale: dry powder inhalation of CRISPR-Cas9 lipid nanoparticles for the treatment of lung diseases. - Simone P Carneiro;Antonietta Greco;Enrica Chiesa;Ida Genta;Olivia M Merkel - Expert opinion on drug delivery (2023)
  8. Recent advances in the delivery and applications of nonviral CRISPR/Cas9 gene editing. - Frazer Sinclair;Anjuman A Begum;Charles C Dai;Istvan Toth;Peter M Moyle - Drug delivery and translational research (2023)
  9. Spatial Transcriptomics: Technical Aspects of Recent Developments and Their Applications in Neuroscience and Cancer Research. - Han-Eol Park;Song Hyun Jo;Rosalind H Lee;Christian P Macks;Taeyun Ku;Jihwan Park;Chung Whan Lee;Junho K Hur;Chang Ho Sohn - Advanced science (Weinheim, Baden-Wurttemberg, Germany) (2023)
  10. Recent Advances in Site-Specific Lipid Nanoparticles for mRNA Delivery. - Xiao Xu;Tian Xia - ACS nanoscience Au (2023)

... (72 more literatures)

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