Meninges as an overlooked pharmacological target for Globoid Cell Leukodystrophy

Globoid cell Leukodystrophy Disease (GLD) is a neurodegenerative life-threatening disease caused by genetic defects in the lysosomal enzyme galactosylceramidase (GALC). It involves dysfunctional metabolism of sphingolipids and is inherited in an autosomal recessive pattern. GLD manifests early in life (3 months to 6 years) with rapid progression (within 2 years) (Wenger DA et al. Hum Mutat 1997). There is no cure for GLD. Treatment options are still very poor (Kohlschutter A. Handb Clin Neurol 2013). Here, we consider GLD pathogenesis and therapy from an entirely new angle, evaluating GLD neurodegeneration and therapy by changing the focus from the neurons and oligodendrocytes to the non-parenchymal brain cells. Specifically, we studied the involvement of meninges in GLD pathogenesis and progression. Meninges are highly heterogeneous tissue with trophic, immune and neurogenic properties (Bifari et al Cell Stem Cell 2017). In this Telethon project, we assessed GLD-induced activation of meningeal immune cell and neural precursors in a mouse model of GLD at pre-onset, onset and late stage of the disease. We found at very early disease stage (pre-onset) a GLD-induced activation in meninges consisting of several immune cell types increased, including monocytes and neutrophils. Moreover, GLD-induced increase and modification of the distribution and phenotype of NPCs present in meninges. These data demonstrate, for the first time, that GLD-induced alterations are present in brain meninges before the clinical onset and the neural parenchyma involvement. Furthermore, we performed proof of concept of the efficacy and safety of supra-physiological GALC expression in human neurons derived from somatic adult human meningeal NPCs. LV-GALC transduced human meningeal NPCs, human meningeal derived-neurons, -oligodendrocytes and -brain organoids, which expressed supra-physiological level of GALC showed the maintenance of stem cell and multipotent neural differentiation potential. GALC-overexpressing brain organoids demonstrate self-assembly properties and differentiational potential in neurons, oligodendrocytes and astrocytes. Therefore LV-GALC transduction can be considered a potential therapeutic target for meningeal-directed in vivo gene therapy.