Synthetic promoters enhance gene therapy precision

Gene and cell therapies hold enormous promise, but their success hinges on precise gene expression to ensure both safety and efficacy. Chromatin Bioscience, founded by synthetic biology expert Michael Roberts, is tackling this challenge head-on with its chromatinLENS platform. By pioneering synthetic promoters that enable targeted, controlled gene expression, the company is reshaping the landscape of advanced therapies – making them safer, more effective and easier to manufacture.

A foundation in synthetic biology

Michael Roberts, CEO and Founder of Chromatin Bioscience, brings a wealth of experience to the table. “My background is in synthetic biology, and I’ve spent much of my career developing technologies to advance gene and cell therapies,” he explains. Roberts’ journey includes founding Synpromics, a company that successfully commercialised synthetic promoters, later acquired by AskBio and subsequently by Bayer. After leaving the AskBio/Bayer group in 2021, Roberts established Chromatin Bioscience in late 2022.

“At Chromatin Bioscience, I am fortunate to work alongside former members of my Synpromics team,” Roberts states. “Together, we focus on leveraging our proprietary chromatinLENS platform to design synthetic promoters that enable precise, durable and safe gene expression, unlocking new possibilities in much of the biotech sector. At present we focus on enabling clients in the cell and gene therapy sector.”

The power of chromatinLENS

The cornerstone of Chromatin Bioscience’s innovation is the chromatinLENS platform. “The chromatinLENS platform is at the core of what we do,” says Roberts. This bioinformatics-driven system allows the company to identify highly specific, cell-type-selective regulatory elements from the human genome. These elements are then used to design synthetic promoters tailored to specific cell types or activated in response to specific signals. “This adds a layer of safety to cell and gene therapies as it allows the gene to be expressed only where it needs to be and minimises off-target expression, which reduces the potential for unwanted side effects,” Roberts explains.

One of the key advantages of chromatinLENS is its focus on in vivo activity from the outset. “What sets chromatinLENS apart is that it enables the design of synthetic promoters with in vivo activity in mind right from the start,” says Roberts. “The platform leverages chromatin structure insights predominantly derived from in vivo epigenetics datasets, eliminating the need for in vitro screening of large libraries, which was a key step in the methods we used at Synpromics.”

This streamlined approach significantly accelerates the development process. “Our improved, streamlined, highly efficient approach allows us to deliver a smaller number of active promoters, which makes it feasible for our clients to test in their models, within two months of starting a project,” explains Roberts.

ESO-T01: a landmark achievement

The effectiveness of chromatinLENS is exemplified by its role in the development of ESO-T01, a next-generation CAR-T therapy. “For ESO-T01, this precision was key,” Roberts states. “Using chromatinLENS, we developed a T-cell-specific synthetic promoter that ensures the BCMA CAR transgene is expressed selectively in T cells, enhancing the therapy’s safety and efficacy.” The BCMA CAR transgene refers to a genetically engineered construct used in CAR-T therapy, specifically targeting B-cell maturation antigen (BCMA),) a protein found on the surface of certain immune cells, including plasma cells.

ESO-T01 stands out as the first in vivo BCMA CAR-T candidate to reach clinical development. “Unlike traditional ex vivo CAR-T approaches, where cells are modified outside the body and then reinfused, ESO-T01 delivers a lentiviral vector directly into the patient, targeting T cells in vivo, eliminating the need for complex manufacturing and logistics.”

The success of ESO-T01 is a significant validation for Chromatin Bioscience. “Our synthetic promoter played a crucial role by enabling precise, durable expression of the CAR construct ONLY in T cells, which is pivotal in reducing off-target effects,” Roberts emphasises. “For Chromatin Bioscience, this milestone validates our technology’s potential and demonstrates how synthetic promoters can transform the safety and scalability of cell and gene therapies.”

Enhancing precision and safety

The precision and safety of gene expression are paramount in gene and cell therapies. Synthetic promoters play a vital role in achieving these goals. “Synthetic promoters act as finely tuned switches for gene expression,” Roberts explains. “By using highly specific regulatory elements, they ensure that therapeutic genes are activated only in the desired cell types, minimising the risk of off-target expression.”

This precision is crucial in mitigating adverse effects. “This precision is critical in gene and cell therapies, where unwanted gene expression in non-target cells can lead to adverse effects,” says Roberts.

Furthermore, Chromatin Bioscience’s synthetic promoters offer enhanced expression levels. “Additionally, our synthetic promoters can provide higher expression levels compared to industry-standard promoters, ensuring robust and effective gene expression in the target cells,” Roberts says. “This enhanced expression is particularly valuable in both in vivo and ex vivo therapies, enabling consistent therapeutic outcomes.”

Another crucial advantage lies in the manufacturing process. “Moreoever, during gene therapy vector manufacturing, our promoters are not active in producer cells, which has the added benefit of increasing vector yields by multiple fold,” Roberts explains. “This is because therapeutic gene expression in producer cells can interfere with vector assembly and reduce the amount of vector produced. We have seen several orders of magnitude increase in vector production yields by using our synthetic promoters.”

Addressing key challenges

Chromatin Bioscience aims to tackle significant challenges in cell and gene therapy with its innovative technology. “One of the major challenges in gene therapies is ensuring a safety profile that allows for in vivo applications,” Roberts states.

The company’s synthetic promoters provide an additional layer of precision. “While targeted delivery vectors play an important role, Chromatin Bioscience’s synthetic promoters enable an additional level of precision that makes in vivo gene therapies safer and more effective, ensuring therapeutic genes are expressed only in the desired cell types and significantly enhancing safety and efficacy,” Roberts explains.

Moreover, the technology addresses bottlenecks in ex vivo therapies. “By designing promoters that are inactive in producer cells but remain active in target cells, we eliminate therapeutic payload expression during manufacturing, which can otherwise destabilise viral vectors. This approach increases yields, improving scalability and reducing costs.”

“Our synthetic promoter technology is an enabler for both therapeutic safety and efficacy, while also addressing key challenges in manufacturing and, therefore, availability,” Roberts emphasises. “This dual capability positions our platform as a transformative tool for advancing the next generation of cell and gene therapies.”

AI-powered gene regulation

Chromatin Bioscience is focused on optimised use of its chromatinLENS platform and enhancing its capabilities. “Our focus is on expanding the applications of the chromatinLENS platform, such as in target discovery,” Roberts says.

The company is also leveraging machine learning to further improve its technology. “We are also developing machine learning models to further enhance the capabilities of our platform,” Roberts explains. “This will allow us to significantly reduce the time required to deliver synthetic promoters to clients, with a goal of achieving a turnaround time of just one week. Machine learning can also improve our ability to mine the dark genome for novel regulatory elements, unlocking new opportunities for precise gene regulation.

“In parallel, we are strengthening our collaborations with industry leaders to bring more therapies to clinical development, as seen with ESO-T01 and other ongoing collaborations,” Roberts adds. “By combining innovative technology, strategic collaborations and a commitment to innovation, Chromatin Bioscience is well-positioned to transform the future of gene and cell therapy.”

With a combination of AI-driven innovation, strategic collaborations and a focus on precision gene regulation, Chromatin Bioscience is set to drive the next generation of cell and gene therapies. As the company continues to refine its technology, its impact on the future of medicine is only just beginning.