Obsidian uses Destabilizing Domains (DDs) to enable pharmacologic regulation of the expression of transduced genes. Obsidian’s DDs are small, fully-human protein domains that confer conditional stability to a fused payload protein. In the absence of a specific small molecule ligand the fusion protein is rapidly degraded, whereas in the presence of the ligand, the fusion protein becomes stable and functional.
Obsidian uses this approach to equip engineered cells with controllable functions that can be precisely tuned by the administration of non-immunosuppressive, small molecule medicines that are readily available and dispensed by the treating physician. This approach has many potential advantages over other methods of regulating transgene expression, which largely rely on transcriptional regulation via inducible promoters. The unique benefits of Obsidian’s DD approach include:
Obsidian is using DDs to create cell therapies with regulated cell-surface receptors, secreted cytokines, cytoplasmic, and nuclear proteins. We have designed our two-part therapeutic system – with a synthetic biological cassette in the cell therapy and the small molecule drug that controls the cassette’s activity – to be a simple and elegant method of regulating transgene function that has the potential to unlock the power of adoptive cell transfer in oncology and eventually find broad use in all forms of cell and gene therapy.
Obsidian has taken the original work on destabilizing domains (DDs) performed by our scientific founder, Professor Thomas Wandless, and has substantially advanced the platform. We have created libraries of novel DDs with properties that make them more suitable for therapeutic use, including:
Control of gene expression is a key issue for adoptive immunotherapy because current technologies do not allow titration of the timing or levels of therapeutic activity. This has made many potential applications difficult or impossible to deploy safely and effectively. The lack of tunability also makes it difficult to safely express potent proteins with narrow therapeutic windows or transient expression.
Obsidian’s current focus is Adoptive Cell Therapy (ACT) for cancer, where tremendous progress has been made in recent years but where today’s therapies remain difficult to titrate, control, or modulate. Among the challenges with current approaches are:
Obsidian’s initial areas of drug development include creating synthetic biological cassettes that incorporate controllable functions for inclusion in CAR-T and CAR therapies. In these applications, using DD technology enables control of key functions to improve safety and efficacy in ways that are not possible with existing CAR-T treatments. Our initial programs include: