Study encourages cautious approach to CRISPR therapeutics
Some gene edits may favor cells with cancer-linked mutations

Date:
November 11, 2021
Source:
Sanford Burnham Prebys
Summary:
A comprehensive study has shown that gene editing, specifically
gene knockout (KO), with CRISPR-Cas9 can favor cells with mutated
forms of genes linked to cancer. The findings highlight the need
to monitor patients undergoing CRISPR-Cas9-based gene therapy for
cancer-related mutations.



FULL STORY ==========================================================================
A comprehensive study -- conducted by researchers at Sanford Burnham
Prebys, the National Cancer Institute (NCI) and other groups -- has shown
that gene editing, specifically gene knockout (KO), with CRISPR-Cas9 can
favor cells with mutated forms of genes linked to cancer. The findings highlight the need to monitor patients undergoing CRISPR-Cas9-based
gene therapy for cancer-related mutations. The study was published in
the journal Nature Communications.


==========================================================================
"Our study shows that in many different cell types, CRISPR gene-editing
can confer a selective advantage to cells harboring mutations in genes associated with cancer, such as p53 and KRAS," says co-senior author Ani Deshpande, Ph.D., an assistant professor in the NCI-Designated Cancer
Center at Sanford Burnham Prebys. "We have shown that when CRISPR-Cas9 is
used to edit the genome, cells with cancer-associated mutations are likely
to be selected to survive -- and this is more widespread than scientists previously understood." CRISPR-Cas9 works by creating double-stranded
DNA breaks at specific points in a DNA sequence, allowing scientists
to target and edit specific genes. However, the p53 gene responds to double-stranded breaks by arresting cell growth, meaning that cells that
have undergone CRISPR would grow and divide less effectively. This means
that cells with mutations in the p53 gene can continue to grow and divide normally, giving them a competitive advantage.

The p53 gene stops cell division if a genomic error arises and attempts
to correct the problem. If the error cannot be fixed, p53 will initiate programmed cell death before the cells can become cancerous. This makes
p53 a critical anti-cancer gene and losing its function can make people
more susceptible to tumors.

"The p53 gene is so important that it's actually nicknamed the 'guardian
of the genome,'" says Deshpande.

Computational biologists led by Eytan Ruppin, Ph.D., chief of the
Cancer Data Science Laboratory at the NCI Center for Cancer Research
and co-leader of the study, analyzed p53 responses to double-stranded
breaks in nearly 1,000 human cell lines. In almost every cell type, they
found that after CRISPR-Cas9 KO, cells with normal p53 genes exhibited
slower growth, while those with mutated p53 genes were less affected,
allowing them to grow faster and outcompete the normal cells. They
also found that CRISPR may confer an advantage to cells with other cancer-associated mutations, like those of the KRAS oncogene.

"This is not the first time researchers have shown CRISPR may introduce potentially dangerous changes," says Ruppin, "However, it is the first
time these effects have been demonstrated in so many diverse cells.

The findings point to a need for caution in the use of CRISPR-based
gene therapies, particularly when treating individuals with underlying mutations in p53 or KRAS genes."There are CRISPR therapies being developed
to correct mutations in many human tissues, but as others have noted
before, we need to proceed with caution, because we may be selecting
for cells that carry mutations in key cancer driver genes when using CRISPR-Cas9 editing, and that could be potentially dangerous. However, fortunately and importantly, additional new CRISPR editing techniques
that have been recently developed are much less likely to carry this risk,
if at all," adds Ruppin.

"Early CRISPR techniques generated double-stranded breaks, but more
modern iterations make simpler edits to target DNA," says Deshpande. "If
we use a non- cutting version of CRISPR we are likely to avoid many
of these problems, which could be very good news for patients."
Despite the potential risks, the authors believe that CRISPR remains
an exciting and revolutionary approach and that barriers like this are
not insurmountable. Both senior authors note that promising medical technologies must often overcome hurdles before they are safe enough to
be used in patients.

Additional study authors include Sanju Sinha, Kuoyuan Cheng, Brid M. Ryan
and Ji Luo at the NCI; Mark D.M. Leiserson at the University of Maryland; Karina Barbosa, Prashant Jain, Anagha Deshpande and Ze'ev Ronai at Sanford Burnham Prebys; and Joo Sang Lee at the Sungkyunkwan University School
of Medicine, Republic of Korea. Sanju Sinha, Kuoyuan Cheng and Karina
Barbosa are the co- first authors, making key contributions to this study.

========================================================================== Story Source: Materials provided by Sanford_Burnham_Prebys. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Sanju Sinha, Karina Barbosa, Kuoyuan Cheng, Mark D. M. Leiserson,
Prashant Jain, Anagha Deshpande, David M. Wilson, Bri'd M. Ryan,
Ji Luo, Ze'ev A. Ronai, Joo Sang Lee, Aniruddha J. Deshpande,
Eytan Ruppin. A systematic genome-wide mapping of oncogenic mutation
selection during CRISPR-Cas9 genome editing. Nature Communications,
2021; 12 (1) DOI: 10.1038/s41467-021-26788-6 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/11/211111080332.htm

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