New CSIRO software aims to increase gene therapy safety for medical and biosecurity applications

By CSIRO AEHRC Transformational Bioinformatics Group Leader Dr Denis Bauer

There are an average of two million differences, or ‘mutations’, in our DNA that make us unique, but some of these mutations can lead to diseases such as cystic fibrosis. In the future, gene therapy may be used to correct these harmful mutations, using genome editing machinery such as CRISPR to correct mutations in affected organs and prevent disease.

In a paper just published in BMC Biotechnology, researchers at CSIRO’s Australian e-Health Research Centre have demonstrated that our unique mutations, or “mutation profile”, can make developing generic gene therapy approaches harder than initially assumed. The paper found this is because our mutation profiles may affect the genome editing machinery’s ability to target the correct site in our DNA – similar to attempting to send mail to a house that has been redeveloped into an apartment block, and the mail being delivered to no-one or a random apartment. This could potentially have harmful side-effects as a person’s mutation profile could have created a new target site near a gene that was not intended for editing.

As detailed in the paper, CSIRO has now developed a computational tool, VARSCOT, that can be used to find the safest target site for each individual by taking their unique mutation profile into account. This can reduce the risk of editing machinery changing the wrong gene and having unintended consequences in gene therapy applications. This approach can also help to develop generic treatments by optimising sites that would work for the majority of the population.

Besides its medical applications, VARSCOT could also be valuable in the biosecurity space. Researchers here and around the world are beginning to explore the possibility of using new genetic approaches to control feral pest animals (e.g. rats, mice, cane toads) or the insect vectors for diseases of humans or domesticated animals, such as malaria. VARSCOT could help determine the right genes to target based on genome sequence information of the pests to ensure the control is effective across the entire population and not affect related species.

VARSCOT is part of the genome engineering toolkit, GT-Scan suite, which CSIRO is developing to support safe and effective genome editing for medical and biosecurity applications.

View the full paper here: “VARSCOT: variant-aware detection and scoring enables sensitive and personalized off-target detection for CRISPR-Cas9“.