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More Damage Detected from Crispr-Cas9 Edits

Crispr genome edits illustration


17 July 2018. A genetics lab in the U.K. revealed that a leading technique for editing genomes produces more unwanted damage to the edited genomes than previously understood. Researchers from the Wellcome Sanger Institute in Hinxton, England report their findings in yesterday’s issue of the journal Nature Biotechnology.

A team from the lab of geneticist Allan Bradley, a former director of the institute, investigated the accuracy and safety of the genome editing technique known as Crispr, short for clustered regularly interspaced short palindromic repeats. Crispr is a method for editing genomes based on bacterial defense mechanisms that use RNA to identify and monitor precise locations in DNA. The actual editing of genomes with Crispr in most cases uses an enzyme known as Crispr-associated protein 9 or Cas9. RNA molecules guide the editing enzymes to specific genes needing repair, making it possible to address root causes of many diseases.

Since Crispr emerged from academic studies in 2011 and 2012, researchers are advancing the techniques into a range of applications in health care and agriculture, including experimental treatments for inherited diseases, HIV, and cancer. The authors identified 6 clinical trials of Crispr-related treatments underway at the time of publication. While previous reports indicate the Crispr-Cas9 technique is safe and precise, with limited other damage from the edits, several other studies cited by the authors raise questions about the accuracy of the technique. Those individual studies, however, are based on specific regions of plant or animal genomes, or cancer cells with abnormal mutations, making it difficult to generalize from their findings.

Bradley, with colleagues Michael Kosicki and Kart Tomberg, performed a more comprehensive analysis of Crispr-Cas9 edits in embryonic stem cells and precursor blood-producing cells in mice, as well as human cell lines. The researchers used comprehensive genomic sequencing techniques to identify and amplify any changes in the target DNA after Crispr-Cas9 editing. The results show Crispr edits using Cas9 enzymes with single-guided RNA result in unwanted insertions and deletions in the edited genomes. In some cases, the unwanted genomic changes occur over a wide range of genes, and in other cases some distance from the original edits, making them difficult to detect.

When editing stem cells, note the authors, this extent of damage could have continuing consequences as the stem cells transform into functioning cells, thus the need for extensive testing with long-range and comprehensive sequencing, instead of the short-range assessments often used today. “This is the first systematic assessment of unexpected events resulting from Crispr-Cas9 editing in therapeutically relevant cells,” says Bradley in a Wellcome Sanger Institute statement, “and we found that changes in the DNA have been seriously underestimated before now. It is important that anyone thinking of using this technology for gene therapy proceeds with caution, and looks very carefully to check for possible harmful effects.”

As reported by Science & Enterprise in June, the original developers of Crispr-Cas9 editing at University of California in Berkeley and in Europe were awarded a U.S. patent for the technique, ending a long intellectual property battle with the Broad Institute, a research center affiliated with MIT and Harvard University. Broad Institute researchers, however, are investigating a different editing enzyme called cpf1, which they say is simpler, smaller and more precise than Cas9. MIT and Harvard University, Broad’s parent institutions, were awarded a European patent for Crisper-cpf1 genome editing in 2017.

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