Mechanisms underlying disease heterogeneity in children with leukodystrophy

Leukodystrophies are genetic, degenerative disorders of myelin that primarily affect children, leading to significant morbidity and mortality. Hypomyelination with Brainstem and Spinal cord involvement and Leg spasticity (HBSL) is the most common leukodystrophy affecting white matter. The progression of HBSL symptoms is linked to survival, yet the underlying mechanisms remain unknown. Previous studies have focused on oligodendrocytes but overlooked the heterogeneity of HBSL pathology. Understanding the cellular and molecular mechanisms is crucial for developing treatments, yet progress is hindered by the lack of human models that recapitulate oligodendrogenesis. This project leverages advances in organoid technology to generate myelinating oligodendrocytes, neurons, astrocytes, and microglia in cortical organoids, an ideal model for human oligodendrogenesis. Using organoids and spatial transcriptomics, we will map cell-to-cell interactions to determine how these networks drive HBSL progression and whether they can be targeted to prevent demyelination. Lastly, we will test guanabenz and aspartate supplementation as potential therapies to reverse HBSL pathology, with implications for other ARS-related leukodystrophies.

Hamad Bin Khalifa University (HBKU)