Hematopoietic Stem Cell Therapies for X-Linked Adrenoleukodystrophy

X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder caused by mutations in the ABCD1 gene, leading to accumulation of very long-chain fatty acids in the nervous system, adrenal cortex and testes. Clinically, the childhood cerebral form is characterised by rapid neuroinflammation and demyelination, whereas adrenomyeloneuropathy presents with more indolent spinal cord degeneration. Hematopoietic stem cell (HSC) therapies aim to replace defective microglial precursors with cells expressing functional ABCD1, thereby arresting inflammatory demyelination and restoring metabolic balance. Traditional allogeneic transplantation has demonstrated efficacy when performed before advanced neurological decline, yet is constrained by donor availability, conditioning toxicity and graft-versus-host risk. Autologous gene-corrected HSC approaches—using lentiviral vectors to deliver a functional ABCD1 cassette—have emerged to address these limitations, offering reduced immunological complications and the possibility of early intervention. Conditioning regimens continue to evolve towards reduced intensity, mitigating toxicity while preserving engraftment. Ongoing clinical observations indicate that timely intervention stabilises white matter integrity, improves endocrine function and enhances long-term neurological outcome. Future directions include optimisation of vector design, safer conditioning protocols and broader access through newborn screening and international collaboration.

Research from Nature Portfolio

Recent studies have demonstrated that autologous HSCs transduced with a lentiviral vector encoding ABCD1 can engraft robustly in the cerebral vasculature and perivascular spaces, leading to sustained normalisation of white matter microvascular permeability and flow. Data reveal an inverse relationship between vector copy number and lesion progression, suggesting that higher levels of gene correction correlate with long-term stabilisation of cerebral demyelination. These findings provide proof of concept that gene-corrected HSCs not only deliver metabolic rescue but also promote remodelling of the neurovascular unit.

Hematopoietic Stem Cell Therapies for X-Linked Adrenoleukodystrophy publication trend

The graph below shows the total number of articles in hematopoietic stem cell therapies for x-linked adrenoleukodystrophy across all publications each year (not limited to Nature Index journals).

Technical terms

Hematopoietic stem cell (HSC): A multipotent progenitor in bone marrow or peripheral blood that gives rise to all blood and immune cells.

Allogeneic transplantation: Transfer of HSCs from a genetically matched donor to the patient.

Autologous gene therapy: Harvesting a patient’s own HSCs, correcting the genetic defect ex vivo, and re-infusing the modified cells.

Lentiviral vector: A viral delivery system engineered to insert therapeutic genes into host cell genomes with long-term expression.

Conditioning regimen: Pre-transplant chemotherapy and/or radiation administered to suppress the recipient’s immune system and create space for donor or corrected cells.

White matter microvascular function: The integrity and permeability of small blood vessels supplying the brain’s myelinated regions.

References

1. Hematopoietic stem-cell gene therapy is associated with restored white matter microvascular function in cerebral adrenoleukodystrophy. Nature Communications (2023).
2. X‐linked adrenoleukodystrophy: Pathology, pathophysiology, diagnostic testing, newborn screening and therapies. International Journal of Developmental Neuroscience (2020).
3. X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management. Orphanet Journal of Rare Diseases (2012).