A powerful new genome editing technique is enabling researchers to replicate human diseases with unprecedented accuracy, promising to revolutionise the drug discovery process for a range of cancers.

Advanced by a WEHI team, the technology can activate any gene – including those that have been silenced – allowing new drug targets and causes of drug resistance to be explored on an unmatched level.

Researchers have leveraged the unique technology to replicate an aggressive form of lymphoma, which they used to identify a gene responsible for triggering resistance to the anti-cancer drug venetoclax.

Aggressive blood cancer

Lymphoma is the most common blood cancer in Australia, with around 6500 people diagnosed each year. Double hit lymphoma (DHL) is an aggressive subtype of the disease.

In a first, the research team was able to enhance a genome editing technology, known as CRISPR activation, to accurately mimic DHL.

Project lead Professor Marco Herold said DHL is difficult to treat, in part due to a lack of efficient pre-clinical modelling.

“Without the ability to model a disease, there are limited opportunities to properly test which drugs will be effective for it in the clinic,” said Professor Herold, who established and leads one of Australia’s most advanced CRISPR laboratories at WEHI.

“The technology is a game-changer as it allows us to mimic diseases like DHL and properly test treatments against them for the first time.

“This is significant when you think of the plethora of human diseases that could be better modelled by using this tool.”

The research has sparked international interest, with the WEHI team working closely with researchers from Nanjing University (China) and Genentech (US), a member of the Roche Group, to develop the technology.

Engineering resistance

Venetoclax is the result of a research collaboration between WEHI and companies Roche, Genentech (a member of the Roche Group) and AbbVie, and is based on groundbreaking scientific discoveries made at the Institute over three decades. It was developed by Roche, Genentech and AbbVie.

The drug is based on a discovery made at WEHI in the late 1980s, that a protein called BCL-2 helps cancer cells survive indefinitely.

A1 is a pro-survival protein of the BCL-2 family that had been thought to play an important role during cancer progression. This had remained unverified – until now.

Using their new model, the team was able to confirm that A1 is a major factor in resistance to venetoclax.

“Our research will allow for more genes to be activated in other models to better understand cancer drivers and, critically, to determine other causes of drug resistance,” project lead Associate Professor Gemma Kelly said.