CRISPR knockout & knock-in mice

A promising new technology?

CRISPR technology is exciting and shows some promising results. One of its potential advantages is that it reduces timelines to generate knockout and knock-in mice. CRISPR does, however, come with drawbacks that still need to be worked out:

CRISPR can produce a high-frequency of off-target events (1,2). The detection and exclusion of CRISPR-induced off-target mutations is challenging due to the numerous off-target sites and subtle nature of the mutations (3). Classical targeting with homologous recombination may produce random integration events, but these are easy to detect and exclude. CRISPR off-target mutations can potentially have a major phenotypic effect; thereby confounding research results produced using CRISPR mouse models.


CRISPR intellectual property is surrounded by a large amount of uncertainty, making licensing for scientists and researchers challenging (4,5).

Due to the reasons and associated risks described above, Ozgene continues to rely on the well-published and proven technique of generating knockout and knock-in mice via classical homologous recombination. At the same time, we are evaluating newer technologies for genome editing, including CRISPR.

Our Senior Staff Scientist attended the Genome Engineering Conference in Nassau, Bahamas. CRISPR was discussed at length during this conference. The mood of the conference was mixed; with a lot of excitement and interest sprinkled with hesitation due to the risk and uncertainty of results and intellectual property issues. As we continue to evaluate the benefits and drawbacks of CRISPR technology for creating knockout and knock-in mice, we will be sure to pass our findings onto you.

REFERENCES:

  1. Fu Y, et al. High-frequency off-target mutagenesis induced by CRISPR-Cas nucleases in human cells. Nat Biotechnol. 31, 822–826 (2013). [read]
  2. Wu, X. et al. Genome-wide binding of the CRISPR endonuclease Cas9 in mammalian cells. Nat. Biotechnol. 32:7, 670–679 (2014). [read]
  3. Kuscu, C. et al. Genome-wide analysis reveals characteristics of off-target sites bound by the Cas9 endonuclease. Nat. Biotechnol. 32:7, 677–683 (2014). [read]
  4. Fong, T. As CRISPR-Cas9 Technology Sets to Take Off, Uncertainty Swirls Around IP Landscape. GenomeWeb Daily News. June 18, 2014. [read]
  5. WOLF GREENFIELD WEBCAST: CRISPR/Cas-9 and the IP Landscape for a Revolutionary New Technology. [watch]

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Ozgene is the innovator in the C57BL/6 strain. Before founding Ozgene in 1999, Dr Frank Koentgen and Dr Gabi Suess were the first to generate and publish C57BL/6 KO mice in 1993.

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