Abstract

TUBB4A-related leukodystrophies are a group of newly described neurodegenerative diseases which are genetic, debilitating, and life-limiting orphan diseases. The incidence is estimated at 1:100,000 to 1:200,000 and makes up 9% of all leukodystrophies. At present, only symptomatic treatments are available as there is no curative treatment. The average life expectancy is about 8 years. TUBB4A-related leukodystrophies are caused by a pathogenic gain-of-function mutation in the TUBB4A gene, which leads to hypomyelination in the white matter of the central nervous system. The most severe diseases include: Hypomyelination with Atrophy of the Basal Ganglia and Cerebellum, hereditary spastic paraplegia, TUBB4A-related isolated hypomyelination, and early infantile encephalopathy. SynaptixBio is developing antisense oligonucleotides to target the pathogenic source of the diseases, by altering TUBB4A mRNA expression. Antisense oligonucleotides are well suited to the treatment of TUBB4A-related leukodystrophies since the absence of Tubb4a expression in mice allowed functional myelination. SynaptixBio has identified a lead antisense oligonucleotide candidate currently in preclinical development, which is expected to improve patient care and outcome.