In this study, we downregulated endogenous transcript levels of leukodystrophy-associated Pol III genes, namely Polr3a, Polr3b, and Polr1c, using small interfering RNAs (siRNA) in primary mouse OL-lineage cells in order to model the hypomorphic effect of variants in a cell-type predicted to be dysfunctional in disease. The gene discussed is POLR3A; the disease is leukodystrophy.