Complex diseases require smarter therapies.
At Senti, we are driven to create medicines that have multiple mechanisms of action, that are targeted and localized, and that can be dynamically controlled. Powered by gene circuits, these therapies are designed to cure even the most challenging diseases.
Multiple Mechanisms of Action
Targeted & Localized
Gene Circuit Engineering: Powering an Entirely New Class of Medicines
Gene circuits are multi-gene constructs that interact to execute a user-defined biological program. Senti’s founding scientists and advisors have programmed gene circuits in living cells to manipulate nearly all aspects of biology. Senti’s broad repertoire of gene circuit technologies allows us to design, build, and test incredible functionality into almost any cell- or gene-based medicine.
- Transcription Factors
- Small Molecule
- Small Molecule
- Optimized Expression
- Logic Gates
- On/Off Switches
- Analog Rheostats
- Kill/Safety Switches
- State Machines
- Genetic Erasers
- Feedback Circuits
Gene Circuits: Deployable into any Cell or Vector
Gene circuits can be deployed into a range of modalities for next-generation cell and gene therapies. We believe that gene circuit therapies will address unmet needs across multiple therapeutic areas.
Building the Future of Cell Therapies for Cancer Patients
We are developing products that overcome key challenges for cell therapies in cancer, both for liquid and solid tumors. Our lead program is focused on overcoming tumor immune evasion via local expression of a powerful combination of immune effectors. In another program, we are working on advanced targeting strategies that more precisely eliminate cancerous cells while sparing healthy cells. We are also developing controlled cell therapies that feature tunable expression of potent payloads in order to drive optimal efficacy within the therapeutic window.
Challenges to Existing Cell Therapy Paradigm
Tumor Immune Evasion
Tumor Antigen Heterogeneity
Limited Therapeutic Window
Senti's Gene Circuit-Enabled Features
Senti's team has pioneered the use of gene circuits for broad therapeutic application. The publications highlighted below represent a sample of the team's innovative and foundational work.
Cho JH, Collins JJ, Wong WW. Universal Chimeric Antigen Receptors for Multiplexed and Logical Control of T Cell Responses. Cell 173:1426 (2018). doi: 10.1016/j.cell.2018.03.038.
Wilson Wong and co-authors introduce a unique split/universal chimeric antigen receptor (CAR) targeting system called SUPRA that affords tunable control over immune cell activity via soluble antigen-binding molecules. SUPRA CAR can fine-tune immune cell activation strength to mitigate toxicity, SUPRA CAR can sense and logically respond to multiple antigens to prevent relapse and enhance safety, and SUPRA CAR can inducibly control cell-type-specific signaling.
Nissim L, Wu MR, Pery E, Binder-Nissim A, Suzuki H, Stupp D, Wehrspaun C, Tabach Y, Sharp PA, Lu TK. Synthetic RNA-Based Immunomodulatory Gene Circuits for Cancer Immunotherapy. Cell 171:1138 (2017). doi: 10.1016/j.cell.2017.09.049.
In this publication, Tim Lu and co-workers present a proof-of-concept immunomodulatory gene circuit platform that enables tumor-specific expression of immunostimulators. Tumor-specific expression was achieved using synthetic cancer-specific promoters and an RNA-based AND gate that generates combinatorial immunomodulatory outputs only when two promoters are mutually active. In preclinical models, a lentiviral cancer gene therapy encoding this gene circuit triggered tumor-specific expression, recruitment of T cells, and immune-mediated elimination of tumors.
Scheller L, Strittmatter T, Fuchs D, Bojar D, Fussenegger M. Nature Chemical Biology 14:723 (2018). doi: 10.1038/s41589-018-0046-z.
Here, Martin Fussenegger and coworkers describe a novel generalized extracellular molecule sensing (GEMS) protein architecture that, working in conjunction with synthetic promoters, can be adapted to detect a wide diversity of inputs including soluble signals. Examples of input signals detected here include the synthetic azo dye, nicotine, a peptide tag, and the PSA (prostate-specific antigen) biomarker.
Schukur L, Geering B, Charpin-El Hamri G, Fussenegger M. Implantable synthetic cytokine converter cells with AND-gate logic treat experimental psoriasis. Science Translational Medicine 7:318 (2015). doi: 10.1126/scitranslmed.aac4964.
Psoriasis is a chronic inflammatory skin disease characterized by a relapsing-remitting disease course and correlated with increased expression of proinflammatory cytokines, such as tumor necrosis factor (TNF) and interleukin 22 (IL-22). Psoriasis is hard to treat because of the unpredictable and asymptomatic flare-up, which limits handling of skin lesions to symptomatic treatment. Here, Martin Fussenegger and colleagues designed a mammalian cell synthetic cytokine converter that quantifies psoriasis-associated TNF and IL-22 levels using serially linked receptor-based synthetic signaling cascades, processes the levels of these proinflammatory cytokines with AND-gate logic, and triggers the corresponding expression of therapeutic levels of the anti-inflammatory/psoriatic cytokines IL-4 and IL-10, which have been shown to be immunomodulatory in patients.
A programmable synthetic lineage-control network that differentiates human IPSCs into glucose-sensitive insulin-secreting beta-like cells
Saxena P, Heng BC, Bai P, Folcher M, Zulewski H, Fussenegger M. A programmable synthetic lineage-control network that differentiates human IPSCs into glucose-sensitive insulin-secreting beta-like cells. Nature Communications 7: 11247 (2016). doi: 10.1038/ncomms11247.
While recent advances in regenerative medicine have permitted the generation of off-the-shelf tissue grafts suitable for a wide variety of medical applications, the low efficiency and high cost of cellular differentiation protocols represent significant hurdles. In this work, Martin Fussenegger and coworkers describe a gene circuit approach that relies on low-cost inputs (like vanillic acid, a relative of the primary extract component of vanilla bean) to efficiently control the derivation of functional pancreatic insulin-producing cells from precursor cells for the treatment of Type 1 diabetes.