We have developed a platform in which we design RNA-encoded programmable genetic “circuits” that detect molecular cues in a cell to specifically express a payload protein in cells that exhibit a particular molecular signature. We applied this platform to the development of our program which entails systemic delivery of lipid nanoparticle (LNP)-encapsulated mRNA-bearing programmable genetic circuitry that selectively expresses a therapeutic payload within target cells.

Cancer immunotherapy has demonstrated robust efficacy but still faces significant challenges when treating solid tumors. To potentially overcome major challenges, we have developed a synthetic cancer-targeting gene circuit platform that enables a tumor-localized combinatorial immunotherapy: a Trojan horse-like approach. Once the circuits enter cells, they will sense the activity of several cancer-associated transcription factors, and get activated in cancer cells, while potentially keeping normal cells unharmed. The circuits trigger robust therapeutic efficacy in vivo in ovarian cancer mouse models. This platform can be adjusted to treat multiple cancer types and can potentially trigger any genetically-encodable immunomodulators as therapeutic outputs.

Constitutive mammalian gene expression relies on a limited collection of natural promoters that drive discrete levels of transcription. Nevertheless, the activities of many natural promoters could often be unpredictable in different species and cell types, making it difficult to precisely control transgene expression. To address these obstacles, using synthetic biology toolkits, we and others have developed versatile, scalable synthetic promoter platforms and programmable genetic components to transform the regulation of mammalian transcription and transgene expression.

Manifold has developed an in vivo protein multiplexing platform, using a proprietary protein barcoding technology (mCodes), and is now leveraging it to engineer tissue-specific biologics with optimal profiles. We share several case studies using our platform across diverse therapeutic areas, including neuro and metabolic disease. We have applied this platform to screen 1000s of brain-shuttle candidates in vivo, resulting in shuttles against unique, novel blood-brain barrier (BBB) receptors (“portals”). In another program, we have further leveraged the platform to engineer binders to metabolically relevant tissues.