Unravelling neuron-glia interactions in Wolfram syndrome through optic nerve-on-chip and in vivo base editing

Wolfram syndrome (WS) is a rare hereditary disease, caused mainly by recessive mutations in the Wolfram syndrome 1 (WFS1) gene. It is characterized by endocrine abnormalities and neurodegeneration, including optic nerve atrophy. MRI of patients and mice demonstrated white matter changes (mainly oligodendrocyte dependent) and volume loss (mainly caused by loss of neurons). Oligodendrocyte and astrocyte abnormalities were also found in WFS1 mutant mice by the Moons/De Groef and Verfaillie groups. As monogenic diseases could be treated by genome editing, it is important to identify the target cell to be edited. In this project, I aim to develop an in vitro optic nerve-on-chip model comprising of iPSC derived retinal ganglion cells (RGCs), oligodendrocytes and astrocytes to understand the role of glial cells (oligodendrocytes and astrocytes) in mediating neurodegeneration in WS. This insight will then be exploited in an in vivo WS rodent model, wherein proof of principle will be obtained for using base editing meditated correction of the WFS1 mutation in the optic nerve. WS will be used as a prototype genetic model for optic nerve atrophy, but the applications of the in vitro optic nerve model to be developed as well as the in vivo base editing approach will have broad applicability to study and / or treat other genetic (and non-genetic) neurodegenerative disorders.