Therapeutic suppression ofTubb4arescues H-ABC leukodystrophy

Abstract

AbstractHypomyelination and atrophy of basal ganglia and cerebellum (H-ABC) is a rare leukodystrophy associated with causal variants in β-tubulin 4A (TUBB4A). The recurring variant p.Asp249Asn (D249N) presents in infancy with dystonia, communication deficits, and loss of ambulation during the first decade of life. In this study, we characterized a genetic murine series (Tubb4aKO/KO,Tubb4aD249N/+,Tubb4aD249N/KO,andTubb4aD249N/D249N) to demonstrate that disease severity correlates with the expression of mutant Tubb4a and relative preservation of WT tubulin. To further evaluate the translational potential ofTubb4asuppression as a therapy in H-ABC, we identified a well-toleratedTubb4a-targeted antisense oligonucleotide (ASO) candidate that selectively reduces Tubb4ain vitroandin vivo. Notably, single intracerebroventricular (i.c.v.) administration of ASO in postnatalTubb4aD249N/KOmice drastically extends its lifespan, improves motor phenotypes, and reduces seizures. Neuropathologically, ASO treatment inTubb4aD249N/KOmice restores myelin and oligodendrocyte survival. Furthermore,in vivovisual evoked potential latencies recover in ASO-treatedTubb4aD249N/KOmice. This is the first preclinical proof-of-concept forTubb4asuppression via ASO as a disease-modifying therapy for H-ABC.