Scientific Publications

Senti Bio's team is pioneering the use of gene circuits for potentially broad therapeutic application. The publications highlighted below represent a sample of the team's innovative and foundational work.

Presented at International Society for Cell and Gene Therapy (ISCT) Virtual Annual Meeting: May 26-28, 2021.

Dharini Iyer, Wesley Gorman, Carmina Blanco, Travis Wood, Mario Lorente, Charity Vilchez Juang, Denny Nguyen, Brandon Lee, Brett Kiedaisch, Philip Lee

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Presented at International Society for Cell and Gene Therapy (ISCT) Virtual Annual Meeting: May 26-28, 2021.

Travis Wood, Abla Bakir, Carmina Blanco, Dharini Iyer, Brett Kiedaisch, Wesley Gorman, Mario Lorente, Brandon Lee, Denny Nguyen, Philip Lee

 

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Presented at American Society of Gene & Cell Therapy (ASGCT) 24th Annual Meeting: May 11-14, 2021.

Michelle Hung¹, Divya Israni², Huishan Li², Yin Yin Chong¹, Poornima Ramkumar¹ , Allison Drain², Allison Quach¹, Mengxi Tian¹, Rishi Savur¹, Niran Almudhfar¹, Chen Ting Lee¹, Abla Bakir¹, Edwin Cruz¹, Carmina Blanco¹, Travis Wood¹, Mario Lorente¹, Brandon Lee¹, Brett Kiedaisch¹, Russell M. Gordley¹, Marcela Guzman Ayala¹, Ahmad Khalil¹, Gary Lee¹, Tim Lu¹

¹Senti Biosciences, Inc.
²Boston University

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Presented at American Society of Gene & Cell Therapy (ASGCT) 24th Annual Meeting: May 11-14, 2021.

Brian S. Garrison, Han Deng, Gozde Yucel , Nicholas W. Frankel, Marcela Ayala Guzman, Russell M. Gordley , Michelle Hung, Derrick Lee, Marcus Gainer, Kathryn Loving, Jenny Chien , Tiffany Pan, Wesley Gorman, Nelia Leemans , Alice Lam, Travis Wood, Wilson Wong, Philip Lee, Tim Lu, Gary Lee

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Presented at American Society of Gene & Cell Therapy (ASGCT) 24th Annual Meeting: May 11-14, 2021.

Nicholas W. Frankel¹*, Seunghee Lee²*, Derrick Lee¹, Marcus Gainer¹, Brian S. Garrison¹, Travis Wood¹,Wesley Gorman¹, Russell Gordley¹, Marcela Guzman Ayala¹, Tim Lu¹, Gary Lee¹, Wilson Wong²

Our iCAR-based NOT GATE gene circuit can significantly reduce CAR-based NK cell killing by >50% in response to recognition of a Safety Antigen that signifies a healthy cell.

¹Senti Biosciences, Inc.
²Boston University
*Equal contribution

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Presented at American Association for Cancer Research (AACR) Virtual Annual Meeting on April 10, 2021.

Alba Gonzalez-Junca, Assen Roguev, Brian Garrison, Nicholas Frankel, Derrick Lee, Marcus Gainer, Alyssa Mullenix, Russell Gordley, Kathryn Loving, Jenny Chien, Gary Lee

We discovered and validated EMCN as Safety Antigen to pair with Flt3/CD33 tumor targeting for the treatment of AML, and developed and tested NOT gate inhibitory circuits that work in an antigen-dependent manner in AML models.

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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.

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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.

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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.

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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.

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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. 

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