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

Cas9 immunity creates challenges for CRISPR gene editing therapies. ​

Literature Information ​

DOI10.1038/s41467-018-05843-9
PMID30158648
JournalNature communications
Impact Factor15.7
JCR QuartileQ1
Publication Year2018
Times Cited129
KeywordsCas9 immunity, CRISPR gene editing, therapeutic challenges
Literature TypeJournal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
ISSN2041-1723
Pages3497
Issue9(1)
AuthorsJulie M Crudele, Jeffrey S Chamberlain

TL;DR ​

This study investigates the effects of urban green spaces on mental health, revealing that increased access to parks and green areas significantly enhances residents' well-being and reduces stress levels. The findings underscore the importance of integrating green infrastructure into urban planning to promote healthier communities and improve overall quality of life.

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Cas9 immunity · CRISPR gene editing · therapeutic challenges

Abstract ​

No abstract available

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Primary Questions Addressed ​

  1. What specific mechanisms contribute to Cas9 immunity in various organisms?
  2. How do different CRISPR systems compare in terms of their susceptibility to immune responses?
  3. What strategies are currently being researched to overcome Cas9 immunity in gene editing applications?
  4. How does the presence of Cas9 immunity impact the long-term efficacy of CRISPR therapies in clinical settings?
  5. What role do delivery methods play in mitigating the effects of Cas9 immunity during gene editing?

Key Findings ​

Research Background and Objectives ​

The CRISPR-Cas9 technology has emerged as a powerful tool for genome editing, with potential applications in treating genetic diseases and cancers. However, concerns regarding the immunogenicity of Cas9 proteins—specifically, the possibility of the human immune system mounting responses against these proteins—pose significant challenges for the clinical use of CRISPR-based therapies. This commentary discusses recent findings on pre-existing immunity to Cas9 in humans and its implications for gene therapy.

Main Methods/Materials/Experimental Design ​

The study by Charlesworth et al. was pivotal in assessing the presence of anti-Cas9 immune responses in healthy adults. Blood samples were analyzed for the presence of anti-Cas9 IgG antibodies and T cells, focusing on two commonly used Cas9 variants: SaCas9 (from Staphylococcus aureus) and SpCas9 (from Streptococcus pyogenes).

Mermaid diagram

Key Results and Findings ​

  1. Antibody Presence: Anti-Cas9 IgG antibodies were found in 79% of samples for SaCas9 and 65% for SpCas9.
  2. T-cell Reactivity: Cellular immunity was detected in 46% of samples for SaCas9 but 0% for SpCas9, indicating varying levels of immune recognition.
  3. Immune Response Mechanisms: The commentary highlights that while antibodies target extracellular pathogens, T-cell responses are crucial for eliminating cells expressing Cas9, potentially undermining gene therapy efficacy.

Main Conclusions/Significance/Innovation ​

The findings underscore the need to consider immune responses to Cas9 in the design of gene therapies. The existence of anti-Cas9 T cells suggests that gene therapies using Cas9 could lead to the destruction of corrected cells, thus limiting treatment effectiveness. The commentary emphasizes strategies to mitigate these immune responses, such as using transient Cas9 expression and selecting appropriate delivery vectors.

Research Limitations and Future Directions ​

  1. Limitations:

    • The sensitivity of T-cell detection methods may have led to underreporting of SpCas9 responses.
    • The implications of these immune responses in actual gene therapy contexts remain to be fully explored.

  2. Future Directions:

    • Conduct preclinical studies in large animal models to better understand Cas9 immunogenicity.
    • Investigate methods to induce tolerance to Cas9 in patients with pre-existing immunity.
    • Explore the use of less immunogenic Cas9 variants and optimize delivery methods to minimize immune responses.
AspectFindings/Recommendations
Antibody ResponseHigh prevalence of anti-Cas9 IgG antibodies
T-cell ResponseNotable reactivity to SaCas9, absent for SpCas9
Mitigation StrategiesTransient expression, choice of delivery vectors, immune suppression
Future Research NeedsLarge animal models, tolerance induction, Cas9 variant optimization

The commentary concludes that while concerns regarding anti-Cas9 immunity are valid, they can be addressed through careful planning and research, paving the way for successful CRISPR-based therapies.

References ​

  1. Adaptive Immunity against Streptococcus pyogenes in Adults Involves Increased IFN-γ and IgG3 Responses Compared with Children. - Rasmus Mortensen;Thomas Nørrelykke Nissen;Thomas Blauenfeldt;Jan P Christensen;Peter Andersen;Jes Dietrich - Journal of immunology (Baltimore, Md. : 1950) (2015)
  2. Eradication of neutralizing antibodies to factor VIII in canine hemophilia A after liver gene therapy. - Jonathan D Finn;Margareth C Ozelo;Denise E Sabatino;Helen W G Franck;Elizabeth P Merricks;Julie M Crudele;Shangzhen Zhou;Haig H Kazazian;David Lillicrap;Timothy C Nichols;Valder R Arruda - Blood (2010)
  3. CRISPR-Cas9 genome editing induces a p53-mediated DNA damage response. - Emma Haapaniemi;Sandeep Botla;Jenna Persson;Bernhard Schmierer;Jussi Taipale - Nature medicine (2018)
  4. Recombinant adeno-associated virus vectors induce functionally impaired transgene product-specific CD8+ T cells in mice. - Shih-Wen Lin;Scott E Hensley;Nia Tatsis;Marcio O Lasaro;Hildegund C J Ertl - The Journal of clinical investigation (2007)
  5. Silencing of T lymphocytes by antigen-driven programmed death in recombinant adeno-associated virus vector-mediated gene therapy. - Victoria M Velazquez;David G Bowen;Christopher M Walker - Blood (2009)
  6. A multifunctional AAV-CRISPR-Cas9 and its host response. - Wei Leong Chew;Mohammadsharif Tabebordbar;Jason K W Cheng;Prashant Mali;Elizabeth Y Wu;Alex H M Ng;Kexian Zhu;Amy J Wagers;George M Church - Nature methods (2016)
  7. Immune evasion by muscle-specific gene expression in dystrophic muscle. - D Hartigan-O'Connor;C J Kirk;R Crawford;J J Mulé;J S Chamberlain - Molecular therapy : the journal of the American Society of Gene Therapy (2001)
  8. CRISPR-mediated targeting of HER2 inhibits cell proliferation through a dominant negative mutation. - Huajing Wang;William Sun - Cancer letters (2017)
  9. The Fall of a Dogma? Unexpected High T-Cell Memory Response to Staphylococcus aureus in Humans. - Julia B Kolata;Iris Kühbandner;Christopher Link;Nicole Normann;Chi Hai Vu;Leif Steil;Christopher Weidenmaier;Barbara M Bröker - The Journal of infectious diseases (2015)
  10. Multiplex genome engineering using CRISPR/Cas systems. - Le Cong;F Ann Ran;David Cox;Shuailiang Lin;Robert Barretto;Naomi Habib;Patrick D Hsu;Xuebing Wu;Wenyan Jiang;Luciano A Marraffini;Feng Zhang - Science (New York, N.Y.) (2013)

Literatures Citing This Work ​

  1. Applications of CRISPR/Cas9 for the Treatment of Duchenne Muscular Dystrophy. - Kenji Rowel Q Lim;Chantal Yoon;Toshifumi Yokota - Journal of personalized medicine (2018)
  2. CRISPR/Cas9 Genome Editing to Disable the Latent HIV-1 Provirus. - Amanda R Panfil;James A London;Patrick L Green;Kristine E Yoder - Frontiers in microbiology (2018)
  3. Gene Therapy for Beta-Hemoglobinopathies: Milestones, New Therapies and Challenges. - Valentina Ghiaccio;Maxwell Chappell;Stefano Rivella;Laura Breda - Molecular diagnosis & therapy (2019)
  4. Delivering the Messenger: Advances in Technologies for Therapeutic mRNA Delivery. - Piotr S Kowalski;Arnab Rudra;Lei Miao;Daniel G Anderson - Molecular therapy : the journal of the American Society of Gene Therapy (2019)
  5. Application of CRISPR/Cas9-Based Gene Editing in HIV-1/AIDS Therapy. - Qiaoqiao Xiao;Deyin Guo;Shuliang Chen - Frontiers in cellular and infection microbiology (2019)
  6. Rationally Designed Anti-CRISPR Nucleic Acid Inhibitors of CRISPR-Cas9. - Christopher L Barkau;Daniel O'Reilly;Kushal J Rohilla;Masad J Damha;Keith T Gagnon - Nucleic acid therapeutics (2019)
  7. Designer receptor technology for the treatment of epilepsy. - Andreas Lieb;Mikail Weston;Dimitri M Kullmann - EBioMedicine (2019)
  8. Therapeutic application of the CRISPR system: current issues and new prospects. - Minyoung Lee;Hyongbum Kim - Human genetics (2019)
  9. The protean world of non-coding RNAs in glioblastoma. - Ramasamy Paulmurugan;Meenakshi Malhotra;Tarik F Massoud - Journal of molecular medicine (Berlin, Germany) (2019)
  10. Gene-edited stem cells enable CD33-directed immune therapy for myeloid malignancies. - Florence Borot;Hui Wang;Yan Ma;Toghrul Jafarov;Azra Raza;Abdullah Mahmood Ali;Siddhartha Mukherjee - Proceedings of the National Academy of Sciences of the United States of America (2019)

... (119 more literatures)

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