Single Participant Study of an Experimental ASO Treatment for TUBB4A-related Leukodystrophy

This is an interventional study to evaluate the safety and efficacy of treatment with an individualized antisense oligonucleotide (ASO) treatment in a single pediatric participant with a de novo pathogenic gain of function TUBB4A mutation associated with severe leukodystrophy with hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC)

• Antisense oligonucleotide treatment (ASO) (Drug), also known as nL-TUBB4-001: Drug: nL-TUBB4-001; Personalized antisense oligonucleotide

Primary outcomes

• Neurological assessments [Baseline to 24 months]: Change from baseline at 24 months post nL-TUBB4-001 administration in scores on the GMFM88, HINE-1, HINE-2, Bayley-4, and Vineland-3 developmental assessment scales, as well as the Tardieu Spasticity Scale and PedsQL Family Impact Module

Secondary outcomes

• Feeding and swallow evaluation [Baseline to 24 months]: Change from baseline at 24 months post nL-TUBB4-001 administration in assessment of feeding and swallow evaluation.
• Safety and tolerability [Baseline to 24 months]: Safety and tolerability

Sex: All, ages: 4 Years to any

Inclusion Criteria:

* Informed consent/assent provided by the participant (when appropriate), and/or participant's parent(s) or legally authorized representative(s).
* Ability to travel to the study site and adhere to study-related follow-up examinations and/or procedures and provide access to participant's medical records.
* Clinical phenotype and neuroimaging consistent with a diagnosis of TUBB4A-related leukodystrophy/Hypomyelination with Atrophy of the Basal Ganglia and Cerebellum (H-ABC)
* Documented genetic mutation in TUBB4A

Exclusion Criteria:

* Participant has any known contraindication to or unwillingness to undergo lumbar puncture
* Use of investigational medication within 5 half-lives of the drug at enrolment
* Participant has any condition that in the opinion of the Site Investigator, would ultimately prevent the completion of study procedures.

• Florian Eichler, MD, Principal investigator, Massachusetts General Hospital