Rewiring Pathways to Treat T1D

Rewiring Pathways to Treat T1D

Hadeel Saab

Looking beyond biopharmaceutical treatments for T1D and other human diseases, Martin Fussenegger’s lab at ETH Zurich researches the possibility of treatments that include cells engineered using synthetic biology principles.

One of the lab’s papers published in the Nature journal focuses on a therapeutic cell engineering system that repurposes endogenous signaling pathways to promote gene expression by activating native or synthetic promoters. This method using generalized engineered activation regulator, or GEARs, addresses limitations of other designs by being pathway-specific rather than input-specific. 

  • The GEAR toolbox includes GEAR, dCas9 (catalytically dead CRISPR-associated protein 9) and synthetic guide RNA (sgRNA) fused to MS2 coat protein (MCP)-binding loops.
    • Together, this toolbox can reroute a number of pre-existing pathways to activate an interchangeable gene of interest.
      • In GEAR(NFAT), this gene of interest includes a transactivation domain and regulatory domain of NFAT, or nuclear factor of activated T-cells.
  • The study’s focus was on GEAR(NFAT) since NFAT enables rewiring of intracellular calcium signaling, an important second messenger that crosses paths with many other cellular processes.
    • Specifically, GEAR(NFAT) uses the calcium signaling from the T-cell line to become activated.
  • When added to beta-mimetic cells in vitro, the GEAR (NFAT) system increased endogenous insulin gene expression.
    • Thus, insulin expression is activated by membrane depolarization, by way of GEAR(NFAT).

Another recent study from the lab presented a wirelessly-powered device that electrically stimulates engineered electrosensitive human beta cells to promote the release of insulin using this system.

  • The device is wirelessly triggered by an external field generator.
  • In T1D mice, the device was used to restore normal blood glucose levels.

What does this mean for T1D? Fusseneger and his lab provide a novel and exciting avenue for treating the disease that can hopefully be further tested.

Sources

  • Krawczyk, K., Scheller, L., Kim, H., & Fussenegger, M. (2020). Rewiring of endogenous signaling pathways to genomic targets for therapeutic cell reprogramming. Nature communications, 11(1), 1-9.
  • Krawczyk, K., Xue, S., Buchmann, P., Charpin-El-Hamri, G., Saxena, P., Hussherr, M. D., … & Fussenegger, M. (2020). Electrogenetic cellular insulin release for real-time glycemic control in type 1 diabetic mice. Science, 368(6494), 993-1001.

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