So could you explain what this ISR is, um, how it goes wrong in the disease, and why it took time for researchers to recognize it as a druggable target?

Well, vanishing white matter is caused by, uh, mutations in the genes that encode eukaryotic initiation factor 2B, so eIF2B.

And eIF2B is the central regulator of the ISR.

Cells have the ISR to cope with stresses like elevated temperature, misfolded proteins, viral infections, and one of the first steps of the ISR consists of inhibition of eIF2B activity, which then triggers the downstream response with a multitude of stress proteins that either lead to repair or apoptosis of the cell.

In vanishing white matter, mutant eIF2B has a decreased activity, so the downstream ISR is always activated, and it's the constitutive activation of the ISR that drives vanishing white matter.

And then why the brain white matter is selectively vulnerable, that's something that we really don't know.

eIF2B is also conditional for the translation of every mRNA into protein and regulates the general rate of protein synthesis.

Can you tell us a bit more about the safety findings and what they mean for future use of the drug?