Marjo van der Knaap on vanishing white matter

Okay, so you briefly mentioned, um, the stress response there, and if I understand correctly, the integrated stress response, also known as ISR, is central to vanishing white matter disease pathophysiology.

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.

And that makes you realize that in vanishing white matter, mutant eIF2B always has remaining activity.

It's never zero because there will be no protein synthesis and no life.

But we have looked at it in all sorts of way.

Protein synthesis is normal in vanishing white matter, so apparently the remaining eIF2B activity is sufficient to guarantee protein synthesis.

So protein synthesis is not the problem in vanishing white matter.

It's the constitutive activation of the ISR.

But mentioning all this makes clear that eIF2B is so deep in biology that I thought for a long time it was beyond treatment, and that you could not simply change eIF2B activity because it was al- also regulating protein synthesis.

And it's through the mutant mice that we made, we made mutant mice that have vanishing white matter.

It's through those mice that I understood that targeting eIF2B and the ISR was certainly possible.

So it's our mouse work that, that made us realize that.