Top ZONMW grant of 675 k€ for Leukodystrophy research of Marjo van der Knaap c.s.

It was announced this week that a project proposal entitled ‘Disease Mechanisms in Vanishing White Matter: Targets for Theraphy Development ‘was granted by the ZONMW agency for funding in the coming 60 months.

Marjo van der Knaap (Principle Investigator at VUmc) about the research in short:

“Leukodystrophies, genetic brain white matter (WM) disorders, have an overall incidence of >1:7500. Vanishing white matter (VWM) is one of the commonest. It mainly affects children, causing neurological regression with stress- (esp. fever-) provoked episodes of rapid decline, coma, and death. Cerebral WM displays profound myelin lack, scarce astrogliotic scarring, and complete disappearance of all structures. We identified the underlying defect in initiation factor eIF2B, which is indispensable for mRNA translation and a key component of the integrated stress response (ISR) in all body cells. The ISR is also one of the 3 pathways of the unfolded protein response (UPR), which is activated by overload of un- and misfolded proteins in the endoplasmic reticulum.

We developed mutant mouse models replicating human VWM. We showed that WM astrocytes and oligodendrocytes are selectively affected, astrocyte pathology being primary, oligodendrocyte pathology secondary. VWM has regional variation in WM disease severity and repair potential, for which the degree of astrocyte abnormality appears responsible. We showed selective ISR activation in astrocytes and oligodendrocytes. It is unclear whether ISR activation is protective, neutral or detrimental.

No therapy is available for VWM. We work at developing multimodal therapy, including pharmacological approaches. For this, we need to delineate roles of the ISR and astrocytes in VWM pathology and identify molecular targets to modulate ISR activation and astrocyte (dys)function to enhance repair.

This proposal will answer 2 questions: (1) How does the ISR impact VWM? (2) How do VWM astrocytes determine WM disease severity and repair potential? We rely on unique VWM patient and control brain tissue and VWM mice. The project will add ground-breaking novel insight into basic roles of the ISR and astrocyte heterogeneity in VWM, with strong implications for WM pathology and physiology and therapy development.”