Hypomyelination with Brain stem and Spinal cord involvement and Leg spasticity, or HBLS, is a rare genetic disease that affects 1 in 7600 newborns and causes leukodystrophy (white matter disease). Most young patients with HBLS show regression in their ability to move and intellectual disabilities by the age of 3. While we know that DNA mutations in the tRNA synthase gene DARS cause the pathology, the precise molecular and cellular processes that underlie this leukodystrophy remain unclear and no effective therapeutics exist. To address this issue we generated hIPSC stem cells from HBLS patients, gene corrected a subset of these, and now use these cells to make a variety of brain and spinal cord organoids. By subjecting these models to scRNAseq, advanced imaging analyses and spatial transcriptomics we gain novel insights into the pathogenesis of HBSL. These same models are further exploited to identify and test drug treatements and gene therapy for this class of diseases.
