Treatment of TUBB4A-related leukodystrophy with antisense oligonucleotide

Connor Gooley is the first patient ever treated with an n-Lorem ASO for TUBB4A-Related Leukodystrophy, a condition that severely disrupts his nervous system, slows nerve impulses, and impairs his fine motor skills. As a result, Connor cannot speak, walk, sit up on his own, or chew well. Still, he manages to army crawl, propel himself in his wheelchair, and use a gait trainer. He’s also remarkably resilient—rarely crying or complaining despite the daily challenges he faces. In this episode of the Patient Empowerment Program, Connor’s parents, Diana and Mike, share their family’s journey from diagnosis to treatment and reflect on their observations of Connor after more than six months on an n-Lorem discovered and developed treatment. This episode is proudly sponsored by Hongene Biotech.

On This Episode We Discuss:
1:33 Shaking eyes were the first sign of Connor’s rare disease
4:10 An MRI revealed little to no myelin, leading to whole genome sequencing and an eventual TUBB4A genetic mutation diagnosis
7:10 Connecting with another family with the same mutation 10:00 Finding n-Lorem through a ‘seeking patient candidates’ advertisement in a Global Genes annual report
12:26 Contextualizing Connor’s TUBB4A mutation in simple terms
21:19 How rare diseases affect families and creating a new normal
27:41 Receiving treatment in Boston and contemplating the decision to agree to an experimental treatment for their son
32:00 Observations after 6 months on treatment
35:45 n-Lorem has given the Gooley family hope for a better future for Connor

https://www.nlorem.org/connor-gooleys-story-a-first-for-tubb4a-treatment/

Sase S, Hacker JL, Napit PR, Bhagavatula A, Woidill S, D'Alessandro A, Jeffries MA, Almad A, Takanohashi A, Padiath QS, Grinspan JB, Marsh ED, Vanderver A. Therapeutic suppression of Tubb4a rescues H-ABC leukodystrophy. Mol Ther. 2026 May 6;34(5):2923-2943. doi: 10.1016/j.ymthe.2026.01.016. Epub 2026 Jan 20. PMID: 41566774; PMCID: PMC13154311.

Abstract

Hypomyelination 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, and Tubb4aD249N/D249N) to demonstrate that disease severity correlates with the expression of mutant Tubb4a and relative preservation of wild-type 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. Notably, single intracerebroventricular administration of ASO in postnatal Tubb4aD249N/KO mice drastically extends its lifespan, improves motor phenotypes, and reduces seizures. Neuropathologically, treating ASO Tubb4aD249N/KO mice prevents myelin and oligodendrocyte (OL) loss and recovers visual evoked potential latencies in vivo. Furthermore, the microtubule function of Mbp mRNA transport from the OL soma to the myelin sheath is retained. A major limitation we noted is that ASOs fail to target cerebellar granule neurons even with multiple routes of administration in the brain. This is the first preclinical proof-of-concept for Tubb4a suppression via ASO as a disease-modifying therapy for H-ABC.