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Senti Bio Programs “Smart” Cell and Gene Therapies Using Advanced Gene Circuit Technology Platform

Synthetic biology is a field that seeks to reprogram biology and has been growing by leaps and bounds since the 2000s. For those of us who have been working in the field since the start, it’s gratifying that going into 2021, the importance of synthetic biology is being seen across a range of diverse and important applications, including therapeutics. Our latest Series B financing round, led by Leaps by Bayer, provides critical resources and validation to drive the application of synthetic biology for cell and gene therapies towards the clinic.

Despite all the progress that has been made, we are just scratching the surface of the potential of synthetic biology to transform the way in which we treat diseases— where cells are the hardware and gene circuits are the software. Our goal is using DNA to program cells to sense disease, adapt, make decisions, and respond with effective treatments—all through the use of “gene circuits.” Whereas CRISPR enables the deletion or editing of DNA to correct disease mutations, synthetic biology enables the creation of new DNA programs that tackle dynamic and difficult diseases, such as cancer.

As an analogy, instead of just using the delete button on your keyboard to edit pre-existing text, we can write entire new genetic stories with the rest of the keyboard using synthetic biology. Our vision is to engineer these “gene circuits” into cell and gene therapy products to implement computer-like logic for increased efficacy, precision and control. Gene circuits are unique combinations of DNA that can direct cells to execute novel programs, such as sensing multiple disease targets, performing logic, and producing combination therapies to achieve enhanced efficacy and safety.

Our growing ability to design cellular programs is even more exciting in the context of recent clinical successes in the cell and gene therapy space, where pioneering clinician-scientists have begun to demonstrate long-term efficacy against previously intractable diseases, often using new modalities, such as adeno-associated viruses (AAV), T-cell therapies, and natural killer (NK)-cell therapies. These first-generation medicines leverage the power of viruses and living cells to reprogram disease in a point-and-shoot fashion. These first-generation approaches are showing success against B-cell cancers and rare genetic disorders where single-target and constitutive (e.g., always on) cell and gene therapies can drive clinical activity while maintaining safety.

However, most diseases aren’t so simple - for example, cancer cells can find numerous ways to escape from individual targeted therapies. And targets that appear to be highly expressed on cancer cells are often also found on normal cells so historically it’s difficult to design drugs that exclusively kill cancer cells without causing significant side effects.

Our vision is to engineer these “gene circuits” into cell and gene therapy products to implement computer-like logic for increased efficacy, precision and control.

This is where synthetic biology comes in. By programming cell and gene therapy modalities that have already demonstrated clinical success, we can upgrade their capabilities to treat diseases in more precise and effective ways. For example, our recent financing will advance our proprietary internal pipeline focused on using allogeneic (off-the-shelf) chimeric antigen receptor natural killer (CAR-NK) cells to address cancers with huge unmet needs. Specifically, our gene circuits enable us to program cells with logic. With SENTI-202, we seek to solve a major challenge in treating acute myeloid leukemia (AML), which is that potential therapeutic targets that are highly expressed on AML cancer cells are also found on healthy bone marrow cells. As a result, conventional drugs that kill cells based only on a single target will cause significant bone marrow toxicity in patients, thus limiting our ability to treat the cancer. To solve this problem, we are designing gene circuits that can detect antigens that are present on healthy cells but not on cancer cells, which serve as a “don’t eat/kill me” signal for our CAR-NK cells. Thus, when these CAR-NK cells detect a tumor antigen alone, they trigger strong killing of cancer cells; however, when these CAR-NK cells detect a tumor antigen and the “don’t eat me” signal together, they spare the target cells, which are healthy cells.

Logic is just one example of how we can apply gene circuit technology to significantly improve disease treatment by precise targeting of diseased cells while sparing healthy tissues. I’ll leave the discussion of other uses of therapeutic gene circuits to future posts. There are numerous other benefits of synthetic biology for enhancing the treatment of solid tumors with cell therapies, as well as enabling improved safety and controllability of these highly potent living medicines. We aren’t just looking at treating cancer with Senti Bio’s gene circuit technology platform, since we believe it can potentially be deployed into diverse therapeutic areas, such as immunology, neurology, cardiovascular disease, regenerative medicine and rare diseases.

As we start 2021, I want to emphasize that none of this would be possible without the team we’ve built here at Senti Bio. It takes a pioneering mentality to do something as groundbreaking as we are setting out to do and I have tremendous gratitude for our employees—both our present team and alumni. With this recent financing, we have the support of new and existing investors, including Leaps by Bayer, to take major strides forward in realizing our mission to outsmart complex diseases with more intelligent medicines.

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