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ARTICLE

CRISPR/Cas9 Gene Editing Tool Found to be "Double-edged Sword"

JUN 13, 2016 | BRIAN P. DUNLEAVY
A vaccine or cure for HIV/AIDS remains the Holy Grail of infectious disease research.

Based on the findings of recent studies, according to a commentary published in the journal Retrovirology and available online at BioMed Central, the discovery of this Holy Grail may still be some ways away.

Researchers at McGill University in Montreal revealed that the gene editing tool known as CRISPR/Cas9, which had previously been shown to hold some promise in removing HIV-infected cells from the human genome, may in fact be a “double-edged sword.” This is because the virus can develop resistance to a CRISPR/Cas9 attack.

“[Studies]… show that, similar to HIV developing resistance to small molecule inhibitors, HIV also develops resistance to CRISPR/Cas9 attack, which calls for further optimization of the CRISPR/Cas9 system to overcome this viral resistance problem,” commentary co-author Chen Liang, MD, an associate professor a McGill’s AIDS Centre, told Contagion. “As a new gene editing tool, more basic and clinical studies are warranted to test the safety of CRIPSR/Cas9 in vivo. Our team is working hard to find solutions to [the problems associated with the tool].”

Indeed, Dr. Liang and his team have concluded that while CRISPR/Cas9 is in fact effective at removing the virus from infected cells, it can also cause the virus to replicate at a much faster rate. Earlier research has also demonstrated that the regenerated DNA is also distinct from the original DNA, which makes the HIV-infected cells resistant to further CRISPR/Cas9 attack. These conclusions build on the findings of two studies performed in the Netherlands and Australia and published earlier this year in the journals Molecular Therapy and Cell Research, respectively.

However, on the bright side, Dr. Liang said, the additional exploration into the potential role for CRISPR/Cas9 has led to increased understanding of how HIV develops resistance to antiviral drugs. He and his colleagues write that “knowing how HIV-1 acquires resistance to Cas9/sgRNA may spur the development of strategies that might overcome this unique viral escape mechanism,” including, perhaps, programming Cas9 with multiple sgRNAs that target conserved viral DNA regions or engineering new Cas9 variants that are able to cleave DNA outside of the target sequence in order to avoid viral resistance. In addition, the development of new CRISPR or CRISPR-like enzymes may also provide a solution.

In their concluding remarks, Dr. Liang et al write that “recognition of the limitations of the CRISPR/Cas9 system will only advance its potential for future widespread application while suggesting strategies for improvement and optimization.” As he noted to Contagion, “In vivo delivery of CRISPR/Cas9 is also a challenge. Fortunately, a variety of viral vectors and delivery systems for gene therapy have been generated and some have already been tested in clinical trials, which can readily be tested for delivering CRISPR/Cas9.” 
 
Brian P. Dunleavy is a medical writer and editor based in New York. His work has appeared in numerous healthcare-related publications. He is the former editor of Infectious Disease Special Edition.
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