Failure of intrathecal allogeneic mesenchymal stem cells to halt progressive demyelination in two boys with cerebral adrenoleukodystrophy

Cerebral adrenoleukodystrophy is an inflammatory demyelinating condition that is the result of a mutation in the X-linked ABCD1 gene, a peroxisomal very long chain fatty acid transporter. Although mutations in this gene result in adrenal insufficiency in the majority of affected individuals, 40% of those affected develop the demyelinating cerebral form, cerebral adrenoleukodystrophy (CALD). CALD is characterized by imaging findings of demyelination and contrast enhancement on magnetic resonance imaging (MRI). Although allogeneic hematopoietic cell transplantation can arrest progression of CALD early in its course, there is no accepted therapy for patients with advanced CALD. Mesenchymal stem cells (MSCs) have been used in a variety of clinical trials to capitalize on their anti-inflammatory properties as well as promote tissue repair. We delivered MSCs via intrathecal (IT) route to two boys with rapidly advancing CALD. The first boy received three doses 1 week apart, whereas the second boy received a single dose of IT MSCs. We note delivery of IT MSCs was feasible and without complication. Follow-up MRI scans after IT MSC delivery showed progressive demyelination in the first patient and no change in demyelination or contrast enhancement in the second patient. Although the infusion of IT MSCs was safe, it did not halt CALD progression in this setting, and future studies should focus on patient selection and dose optimization. Lessons learned Mesenchymal stem cells can be safely delivered to boys with cerebral adrenoleukodystrophy. Advanced cerebral adrenoleukodystrophy may not respond to intrathecal injection. Significance statementCerebral adrenoleukodystrophy (CALD) is characterized by imaging findings of demyelination, inflammation, and contrast enhancement on magnetic resonance imaging (MRI). There is no accepted therapy for patients with advanced cerebral adrenoleukodystrophy. Mesenchymal stem cells (MSCs) were delivered via intrathecal (IT) route to two boys with rapidly advancing CALD in hopes of utilizing their anti-inflammatory ability to halt disease progression. The delivery of IT MSC was feasible and without complication, although follow-up MRI scans after IT MSC delivery showed progressive demyelination in both patients. This may have been due to the advanced nature of disease in the patients or an inadequate cell dose.