Wellcome Sanger Institute scientists warn CRISPR/Cas 9 gene editing could lead to 'harmful effects'
Popular technique could cause genetic damage that standard tests may miss
Changes in DNA caused by one of the newest genome-editing tools have been “seriously underestimated” and could lead to “harmful effects”, Wellcome Sanger Institute scientists have warned.
CRISPR/Cas9 gene editing has been increasingly used by researchers and has been seen as a route to potential treatments for diseases include cancer, HIV and sickle cell disease.
But Sanger Institute scientists have discovered that the technique causes greater genetic damage in cells than previously thought, which has prompted safety concerns over such potential gene therapies.
Professor Allan Bradley, corresponding author on the study published in Nature Biotechnology, said: “This is the first systematic assessment of unexpected events resulting from CRISPR/Cas9 editing in therapeutically relevant cells, 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.”
The study also shows that standard tests for detecting DNA changes miss the genetic damage caused by CRISPR/Cas 9, meaning specific testing will be required for any future therapeutic uses.
CRISPR/Cas9 is like the cut and paste of the genome editing world. It can alter sections of DNA in cells by cutting at specific points and introducing changes at that location. Such editing has been seen as a useful way of inactivating disease-causing genes, or correct genetic mutations.
But the scientists warn any potential treatments will have to prove they are safe.
Previous studies have not shown many unforeseen mutations in the DNA from the technique at the genome-editing target site.
But Sanger Institute scientists investigated this further by carrying out a full systematic study in both mouse and human cells. They found CRISPR/Cas9 frequently caused extensive mutations – but at a greater distance from the target site, meaning they could not be spotted by standard genotyping methods.
Many cells had large genetic rearrangements such as DNA deletions and insertions, which could lead to crucial genes being switched on or off.
Michael Kosicki, the first author from the Wellcome Sanger Institute, said: “My initial experiment used CRISPR/Cas9 as a tool to study gene activity.
“However, it became clear that something unexpected was happening. Once we realised the extent of the genetic rearrangements we studied it systematically, looking at different genes and different therapeutically relevant cell lines, and showed that the CRISPR/Cas9 effects held true.”
The work could have huge implications for the gene-editing community and is expected to renew interest in the search for alternatives methods.
Independent researcher Professor Maria Jasin, from Memorial Slone Kettering Cancer Centre, New York, who was not involved in the study, said: “This study is the first to assess the repertoire of genomic damage arising at a CRISPR/Cas9 cleavage site. While it is not known if genomic sites in other cell lines will be affected in the same way, this study shows that further research and specific testing is needed before CRISPR/Cas9 is used clinically.”
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