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Targeting a central stress pathway

What happens when cells fall out of homeostasis due to stress to the system? Human cells have evolved to handle many types of acute stress, but what happens when the biological machinery in place to maintain homeostasis doesn’t work and stress becomes chronic? Scientists at Calico are very interested in homeostasis in aging and disease because understanding that might lead to the ability to target specific biological pathways involved in the pathology of disease.

Calico scientists led by Carmela Sidrauski, are conducting extensive research on the integrated stress response (ISR) pathway, and specifically eIF2B, which is inhibited when cells sense stress. Prolonged activation of the ISR pathway through eIF2B can cause a breakdown of normal protein synthesis in the cell and ultimately lead to a number of neurological diseases.

Our efforts are focused on understanding the biology of the ISR pathway and translating this work into developing modulators of eIF2B that can restore protein synthesis and inhibit the expression of troublesome stress proteins. We believe these efforts could lead to important breakthroughs in the treatment of a number of diseases and help answer key questions about the biology of aging.

Working closely with our collaborators at AbbVie, we published peer-reviewed papers on preclinical research demonstrating in vivo that our novel small molecule eIF2B activator rescues the activity of the eIF2B complex carrying a mutation that causes the neurodegenerative disorder, Vanishing White Matter Disease (VWMD).

Read the paper here.

See the 2015 press release announcing Calico’s agreement with Peter Walter’s lab at the University of California San Francisco

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