Cellular Prostheses for Psoriasis

With set doses delivered at regular intervals, the conventional approach to treating disease inevitably limits the care of patients whose symptoms fluctuate or progress. For these patients, treatment schedules can change daily and compliance can be an uphill struggle.

Martin Fussenegger, professor of biotechnology and bioengineering at the University of Basel, is proposing a radical solution: “We need therapeutic interventions that perfectly interface with human metabolism – that carefully measure disease markers and produce an adjusted response.”

To provide this perfectly tailored therapy, Fussenegger and his colleagues have engineered designer cells that can monitor circulating disease-associated pro-inflammatory cytokines; process their differential levels; and coordinate in situ production, dosing, and delivery of therapeutic immunomodulatory cytokines. The microencapsulated cells were able to prevent psoriasis flare-ups and treat acute (established) psoriasis in mice, returning skin to normal (1). “The ‘synthetic circuit’ mimics natural control and response dynamics,” says Fussenegger. “After a 15-year track record in designing transgene control systems, we are now able to design complex therapeutic circuits,” he says. “This is a novel treatment concept we call ‘prosthetic networks’ as they replace deficient metabolic pathways – akin to classical mechanical prostheses replacing defective body parts.”

The team serially linked signaling and expression of the cytokine receptors in human cells, so that the TNF receptor triggers expression of an IL22 receptor component. When both psoriasis-specific cytokines TNF and IL22 are present, the cascade induces expression of IL4 and IL10 – two immunomodulatory cytokines.

“The cytokine converter detects pro-inflammatory psoriasis-associated cytokines and treats psoriasis at the same time,” says Fussenegger. A major advantage of the circuit is that it eliminates the need for tablets. Immunomodulatory cytokines have induced rapid improvements in psoriasis patients but with short half-lives in the bloodstream, daily drug dosing is necessary – which can be hard for patients to stick to.

The designer cells were not only effective in mice but were equally responsive to blood samples from psoriasis patients, suggesting that the circuit captures the clinically relevant cytokine range. Fussenegger hopes that in the next decade researchers will be able to implant designer cells that can dynamically interface with the patient’s metabolism, by detecting specific disease metabolites or biomarkers in real time to coordinate immediate production and systemic delivery of protein therapeutics.

“The time has now come to program therapeutic gene networks for various diseases,” state the authors of the paper. “Given the modular configuration of these therapeutic networks, they may be readily tailored within months for a particular disease phenotype and thus provide new opportunities in future gene- and cell-based therapies.”