For Dr Brian Zambrowicz, Vice President of Functional Genomics at Regeneron and chief of its VelociGene operations, CRISPR/Cas9 technology has changed the game in gene editing in fundamental ways, promising significant benefits in both basic research and, potentially, in therapeutics.
“Tools that can be used to create targeted cutting of DNA increase our ability to engineer the genome. This has been possible in the past with older technologies like Zn Finger and TALEN-directed nucleases, but it has become much more broadly applicable with the introduction of CRISPR/Cas9,” he says.
“Because it is incredibly easy to use, flexible and easy to design, it allows scientists to achieve in a matter of days things that used to take much longer. It has many applications in basic research and has great potential as a therapeutic.”
He specifically highlights the use of the technology in drug development but says that, here, gene editing should be integrated into a chain of technologies and combined with a depth of biological understanding, rather than being seen as standing in isolation.
“We’re a company with the foundational belief that genetics drive a lot of diseases,” he says of Regeneron. “If you believe in genetics, you can’t ignore a technology that allows you to modify genes to affect disease. That’s why we are so excited by CRISPR/Cas9 – because gene editing has the potential to actually cure genetic disease.”
He says that many disease-causing mutations and genetic variations associated with disease have been identified that are potential targets for the new technology. Regeneron’s own Genetics Center continues to make new discoveries related to the genetics of human disease.
“All this is providing additional leads on where exactly in DNA we might want to knock out, repair or insert genetic sequences in order to attack diseases that have been historically difficult to address.”
The liver is, he says, a good place to start because it is one of the body’s main production sites for large numbers of proteins and is also ‘amenable’ to current delivery methods.
This is a focus for Regeneron in its collaboration with Intellia, one of the spin-off companies to have emerged from the labs that worked on the foundation IP for the new technology.
Together they are working on transthyretin (TTR) amyloidosis, a severe and ultimately fatal disease that has yet to find an effective treatment. “Using CRISPR/Cas9 we hope to edit the gene causing the dysfunctional TTR, but this is still very early research.”
And, despite the rapid advances that have been made in CRISPR technology in a relatively short time, that note of caution is indicative of the challenges that lie ahead in capturing the potential of this technology.
Brian points to several. Finding better ways to deliver components of CRISPR/Cas9 to specific tissues efficiently and ensuring that off-target DNA cutting is minimised will be key to the safe use of this technology, he says. Just as important is the need to improve target insertion and repair techniques.
“There’s a lot of technology development that needs to happen before we use these treatments in patients.”
But he is confident Regeneron can play an important role in further developing the technology in safe ways. “Regeneron has a long history of gene editing in mouse models and depths of experience in genetic engineering, so we feel well equipped to develop the refinements required for CRISPR/Cas9 to be used safely and effectively for therapeutic development.”