Broken String Biosciences launched an early access program (EAP) through which select developers of gene edited therapeutics will be able to use Broken String’s INDUCE-seq® technology in their own labs for detecting and quantifying both the on- and off-target double strand DNA breaks that occur as a result of CRISPR and other nuclease-based gene editing in cells.
Building on the success of Broken String’s service-based INDUCE-seq lab offering, the new Catalyst program will support integration of the platform into participants’ therapeutics development pipelines at the earliest discovery and optimization stages.
Users will be able to use INDUCE-seq on site to derive precise, real-time identification of exactly where DNA breaks occur, in parallel with the process of iterating on guide RNA designs and optimize delivery systems, and in diverse cell and tissue types.
“The platform enables direct, unbiased genome-wide identification and quantification of the exact position of double strand DNA breaks in edited cells, in clinically relevant samples, to support progression through discovery and preclinical development, and IND application.” Dobbs maintains the EAP will enable broader industry-wide adoption of INDUCE-seq and position the technology as an essential safety component supporting the development of the next generation of gene-edited therapeutics.
In contrast with current platforms, INDUCE-seq is precise and sensitive, PCR free, and cell and nuclease-agnostic. The technology has been developed to solve what the company describes as a fundamental gene editing safety challenge, in that developers need the ability to accurately and reproducibly assess both on- and off-target double strand DNA breaks, genome wide, and at high resolution. The ability to identify and map double strand breaks resulting from a gene edit reproducibly and cost effectively will be crucial for ensuring the efficacy and safety of relevant therapeutics as they progress through development to market, Dobbs commented to GEN.
“There is an imperative to satisfy regulatory scrutiny surrounding CAR-T cell and other gene-edited therapies. Historically companies in this space may have simply predicted where these breaks may occur and monitor them in patients, but to achieve regulatory clearance developers must be able to determine empirically where these sites are.”
Industry has until now lacked a gold standard for detecting on- and off-target edits, Dobbs noted. “Currently there are a handful of technologies, which might be described as “home-brewed” adaptations of methods and protocols published in the literature, but until now there hasn’t really been one standardized technology.” And existing approaches may also present challenges, including PCR-induced bias, and missed rare, low-frequency unintended edits that may be dangerous and could have “disastrous consequences” for clinical programs, he pointed out. “And rare double stranded breaks may not be detected by existing whole genome sequencing approaches.”
Over recent years companies have had access to INDUCE-seq technology via services offered by Broken String at its labs in Cambridge, U.K. Through the Catalyst program, partners will be equipped to set up and run the INDUCE-seq platform within their own labs, giving them the ability to generate results in just days. INDUCE-seq should be within the reach of most conventional lab setups, using standard liquid handling equipment, Dobbs stated.
Participants can then easily conduct repeated assessments as they refine and validate editing strategies, harnessing INDUCE-seq to rapidly identify unintended DNA breaks that might compromise the safety or efficacy of therapies. For instance, therapies targeting rare liver diseases or neurological conditions can be tested for unintended effects on nearby tissues, an increasingly important requirement for regulatory approval. This capability will be especially valuable as gene editing expands to treat complex, multi-gene disorders, where multiple targets and delivery mechanisms must be carefully balanced to minimize risks, the company believes.
In-house application of INDUCE-seq will help to springboard organizations’ ability to negotiate regulatory approval when progressing from preclinical to clinical development, ultimately supporting commercialization of gene-edited therapeutics, Dobbs stressed. The gene editing industry has reached an inflection point, where the momentum required to reach its potential can only be sustained by expanding patient access—which requires standardization, faster drug development, and robust safety characterization, he believes.
Broken String Biosciences
“One of the real challenges faced by the field and one of the things that we are trying to address is that there is no safety standard, and this creates a real uncertainty for companies,” Dobbs explained. “There is a lack of standardization for existing technologies, and organizations are guessing what the FDA will require or accept.”
In contrast with such technologies, INDUCE-seq is both a reproducible and highly precise genome-wide measurement platform for mapping all the break points that can occur in cells naturally as well as through the gene editing process, Dobbs further explained to GEN. “We’ve brought different elements together to address the challenges faced by other technologies that are very slow and laborious. We have developed a novel way of labeling DNA breaks in cells, and then reading them out by sequencing. Using our novel, PCR-free methodology we get a very precise record of those breakpoints and their frequencies in a way that’s relatively easy to do and scalable. Core to how the technology works is our novel way of preparing the libraries for sequencing, and it’s this that gives us this very clean readout, free of PCR. It’s a process-, not equipment-based platform. Through the Catalyst program we will help with set up, and how to feed data into our cloud-based informatics platform.”
Broken String raised a $15 million Series A round of financing in September 2023, which supported the development of its “platform as a service” offering. The exact format of the new Catalyst program is still evolving, Dobbs suggested to GEN, “but the idea is that we will support participants’ implementation of all the lab components and provide access to the cloud-based informatics platform.”
In parallel, Broken String is continuing to evolve its core INDUCE-seq platform. “We aim to adapt as new CRISPR systems are developed,” Dobbs said. “Our technology can also be modified to detect editing from different editing systems, such as base editing. It’s a rapidly evolving field, and we want to be part of the story, in bringing this whole generation of medicines to patients.”
Aside from leveraging use of INDUCE-seq in the development of gene edited therapeutics, Broken String is also working with academia to apply INDUCE-seq in the field of disease research. In 2024 the company set up a partnership with the Francis Crick Institute, through which INDUCE-seq will be harnessed to investigate the impact of genomic instability on the development of amyotrophic lateral sclerosis.
