Sase, S.; Hacker, J. L.; Napit, P. R.; Woidill, S.; Bhagavatula, A.; Alessandro, A. D.; Almad, A.; Takanohashi, A.; Padiath, Q.; Marsh, E. D.; Vanderver, A.

Hypomyelination and atrophy of basal ganglia and cerebellum (H-ABC) is a rare leukodystrophy associated with causal variants in {beta}-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, and Tubb4aD249N/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 of Tubb4a suppression as a therapy in H-ABC, we identified a well-tolerated Tubb4a-targeted antisense oligonucleotide (ASO) candidate that selectively reduces Tubb4a in vitro and in vivo. Notably, single intracerebroventricular (i.c.v.) administration of ASO in postnatal Tubb4aD249N/KO mice drastically extends its lifespan, improves motor phenotypes, and reduces seizures. Neuropathologically, ASO treatment in Tubb4aD249N/KO mice restores myelin and oligodendrocyte survival. Furthermore, in vivo visual evoked potential latencies recover in ASO-treated Tubb4aD249N/KO mice. This is the first preclinical proof-of-concept for Tubb4a suppression via ASO as a disease-modifying therapy for H-ABC.