In this Telethon Project, we will consider Globoid cell Leukodystrophy Disease (GLD) pathogenesis and therapy from an entirely new angle. We will study GLD neurodegeneration and therapy by changing the focus from the neurons and oligodendrocytes to the non-parenchymal brain cells. In particular, we will study the involvement of meninges in GLD pathogenesis and progression. Meninges are highly heterogeneous tissue with trophic, immune and neurogenic properties. Meninges are: - widely distributed into the brain; - a gateway for immune cell access into the CNS and - important source of trophic factors for the brain. Recently, we have identified neural progenitor cell (NPC) population in meninges that migrate to the cortex and differentiate into functional and integrated cortical neurons (Bifari et al Cell Stem Cell 2017).
In this project, we will assess GLD-induced activation of meninges and meningeal NPCs. We will exploit meninges as effective complementary site for GALC gene transfer in GLD. Transduced meningeal cells may provide GLAC secretion to the brain (cross-correction) and GALC-transduced meningeal NPCs can migrate to the brain and differentiate into GALC-overexpressing cortical neurons. Furthermore, we can culture, from adult human meninges, NPCs with neuronal differentiation potential. We will perform proof of concept of efficacy and safety of supra-physiological GALC expression in somatic, human meningeal NPCs (as potential therapeutic target for meningeal-directed in vivo GT).
In this project, we will assess GLD-induced activation of meninges and meningeal NPCs. We will exploit meninges as effective complementary site for GALC gene transfer in GLD. Transduced meningeal cells may provide GLAC secretion to the brain (cross-correction) and GALC-transduced meningeal NPCs can migrate to the brain and differentiate into GALC-overexpressing cortical neurons. Furthermore, we can culture, from adult human meninges, NPCs with neuronal differentiation potential. We will perform proof of concept of efficacy and safety of supra-physiological GALC expression in somatic, human meningeal NPCs (as potential therapeutic target for meningeal-directed in vivo GT).