Therapeutic Gene Editing Safety and Specificity

https://doi.org/10.1016/j.hoc.2017.05.002Get rights and content

Section snippets

Key points

  • Safety of gene editing is closely tied to specificity.

  • Careful design of gene editing tools can improve specificity and thus safety.

  • A high degree of specificity is possible with the new generation of targeted nucleases.

  • Assessing the impact of gene therapy tools during their design, study, and clinical use is essential.

Safety

Safe manipulation of the human genome is paramount to gene therapy because the intended effect of gene therapy is a permanent modification of cell function. Thus, unintended modifications that alter cell function may have long-lasting consequences.

The last decade has seen the rapid introduction of new tools, including zinc finger nucleases, homing endonucleases, transcription activator-like effector nucleases (TALENs), and RNA-guided nucleases that allow for the targeted modification of

Specificity

Critical to the success and safety of targeted endonucleases and other forms of gene therapy is the degree of specificity that can be achieved. The random integration events that occur with retroviral gene delivery demonstrate the danger of gene therapy in the absence of high degrees of specificity. New generations of targeted endonucleases, including zinc finger nucleases, TALENs, and CRISPR/CRISPR-associated endonuclease (Cas) 9, each have unique mechanisms for binding to specific genomic

Summary

Learning from the challenges of the first gene therapy trials, a large emphasis has been placed on improved specificity to achieve safety. The new generation of targeted nucleases has made the possibility of precise genetic manipulation a reality. The purpose of this article is not to endorse a particular platform over another. Each has their merits and all have the potential for safe and effective therapeutic application. Importantly, large-scale cross-platform comparisons of safety and

Acknowledgment

The authors would like to thank Jackie Morton, Seattle Children's Hospital Librarian, for her assistance in conducting a literature search for this submission.

First page preview

First page preview
Click to open first page preview

References (32)

  • H. O'Geen et al.

    A genome-wide analysis of Cas9 binding specificity using ChIP-seq and targeted sequence capture

    Nucleic Acids Res

    (2015)
  • S.Q. Tsai et al.

    GUIDE-seq enables genome-wide profiling of off-target cleavage by CRISPR-Cas nucleases

    Nat Biotechnol

    (2015)
  • B.S. Jones et al.

    Improving the safety of cell therapy products by suicide gene transfer

    Front Pharmacol

    (2014)
  • F.S. Collins

    Statement on NIH funding of research using gene-editing technologies in human embryos

    Natl Inst Health NIH

    (2015)
  • Human genome editing: science, ethics, and governance

    (2017)
  • M. Bibikova et al.

    Targeted chromosomal cleavage and mutagenesis in Drosophila using zinc-finger nucleases

    Genetics

    (2002)
  • Cited by (18)

    • Systemic mRNA Therapy for the Treatment of Fabry Disease: Preclinical Studies in Wild-Type Mice, Fabry Mouse Model, and Wild-Type Non-human Primates

      2019, American Journal of Human Genetics
      Citation Excerpt :

      Therapeutic proteins made from exogenously administered mRNA in the body may mimic the endogenous target protein more closely than recombinant proteins, such as ERTs, which are manufactured from CHO, human, or plant cell lines. mRNA treatment produces transient protein levels, while avoiding genomic integration and the off-target risks of gene therapy or gene editing therapy.22,23 Multiple mRNA-based cancer immunotherapies and vaccines are currently in clinical trials.24

    • Sphingosine phosphate lyase insufficiency syndrome (SPLIS): A novel inborn error of sphingolipid metabolism

      2019, Advances in Biological Regulation
      Citation Excerpt :

      Gene editing technology is developing rapidly and represents a potential therapeutic avenue for SPLIS, as well as all monogenic forms of disease. Problems with off-target effects and efficient delivery in an intact organism remain to be solved, but gene editing remains highly promising (Lux and Scharenberg, 2017). Gene therapy strategies represent another potential therapeutic with the potential to correct all of the biochemical consequences of SPL insufficiency.

    View all citing articles on Scopus
    View full text