CRISPR-based technologies have pushed genome editing therapeutics to new heights, with dozens of companies developing potentially transformative therapies. Alongside the promise come risks—known and unknown—associated with unintended, off-target genome edits. The field needs fast, reliable, accurate, and cost-effective means for measuring double-strand breaks (DSBs) in DNA. Unfortunately, no commercial platform has yet fitted the bill.
Broken String Biosciences is positioning its technology as the gold standard for safety analysis in genome editing therapy. The company’s platform technology is INDUCE-seq (Fig. 1), first developed by co-founders at Cardiff University—including CEO Felix Dobbs, CSO Simon Reed and staff scientist Patrick van Eijk—in a project sponsored by AstraZeneca. Designed to meet the industry need, INDUCE-seq measures DSBs, such as those induced by CRISPR genome editing, with high sensitivity, including low-level off-target edits that can be both hard-to-detect and carcinogenic.
Fig. 1 | Broken String Bioscience’s INDUCE-seq technology. The technology identifies on and off-target DSBs in the genome that are induced by gene editing. DSB, double-strand breaks.
“Fundamentally, the company is built on deep knowledge of DNA repair mechanisms,” said Broken String advisor Stephen Jackson, who is also Senior Group Leader at the Cancer Research UK Cambridge Institute and Associate Group Leader at the Wellcome/Cancer Research UK Gurdon Institute. “INDUCE-seq offers an unbiased way to systematically assess the potential off-target aspects of CRISPR gene editing.”
Rapid progression
In 2020, the founding team took Broken String into the Illumina Accelerator program that helped the spinout move quickly to a $4 million seed financing in September 2021. This enabled the company to grow to 12 people, building recognition through participation in public–private partnerships such as the National Institute of Standards and Technology Genome Editing Consortium, and the Health and Environmental Sciences Institute Cell Therapy—TRAcking, Circulation, & Safety Committee. These consortia helped Broken String’s technology secure international validation and launch commercial operations with early adopters that have already begun to generate significant revenue.
Last year, the co-founders published landmark data showing INDUCE-seq’s ability to measure DSBs with higher specificity and less noise than common PCR-based methods. This momentum led to a recently closed $15 million series A round, co-led by Illumina Ventures and Mérieux Equity Partners.
Broken String’s advance comes not a moment too soon. Genome editing approaches are generating a lot of excitement for their therapeutic potential, with at least 40 companies using a variety of platforms to develop in vivo or cell-based therapies. Several companies have launched clinical trials with therapies based on CRISPR technology, the engine behind the field’s momentum, for diseases ranging from Duchenne muscular dystrophy to cancer. The US Food and Drug Administration (FDA) may approve the first CRISPR-based medicine this year, for sickle cell disease, and regulators have estimated there are more than 1,000 programs in development that will need the kind of safety analysis that Broken String will enable.
Standardizing and reducing risks
For all its promise, genome editing still poses risks. Several trials that leverage genome editing technology have been halted following detection of chromosomal abnormalities or concerns about other off-target edits. In particular, the more established CRISPR-Cas systems edit a genome by cleaving both strands of DNA at an intended target. But these DSBs can occasionally occur off-target, causing unintended edits with carcinogenic potential.
“FDA has made clear they want genome editing companies to identify and characterize off-target editing activity and risks, starting at the preclinical stage,” said Dobbs. “We see a tremendous market opportunity here, because developers have yet to coalesce around a standard for unbiased measurement, and there’s no off-the-shelf product that meets the need.”
Because of the vacuum, therapeutics companies must invest heavily in bespoke internal analytical processes, which becomes challenging when they present data to regulators. “There’s no gold standard, no consistent sense of precisely what is required to demonstrate safety. That leads to really complex conversations with the FDA, which finds it hard to assess them. Our mission is to standardize and expedite that process,” Dobbs said.
Even beyond regulatory concerns, companies are now seeing the value of integrating Broken String’s platform into development—helping them select guide RNAs based on their efficiency, as well as understand and optimize the mechanism of their gene editing process. “Any company using genome editing as a fundamental technology can benefit from INDUCE-seq, at discovery, preclinical or early clinical stages, for in vivo or ex vivo therapies,” Dobbs said.
Jackson agreed. “Broken String is moving toward becoming the go-to company for this sort of assessment,” he said. “Genome editing companies will want their rubber stamp to demonstrate the safety of their therapies.”