Adrenoleukodystrophy

Overview

X-linked adrenoleukodystrophy (X-ALD) is an inherited disorder caused by harmful variants in the ABCD1 gene. The resulting shortage of the ALD protein prevents normal breakdown of very-long-chain fatty acids, which accumulate and damage the adrenal glands, brain, spinal cord, and peripheral nerves. Boys and men are most often severely affected, although many women who carry an ABCD1 variant develop later-life spinal-cord symptoms. Major forms include rapidly inflammatory cerebral ALD (cALD), usually in childhood but also possible in adults, and the more slowly progressive adult spinal-cord disorder adrenomyeloneuropathy (AMN). GeneReviews: X-Linked Adrenoleukodystrophy

Prognosis depends greatly on the form and timing of diagnosis. Untreated childhood cALD can progress from behavioral or learning changes to severe loss of function and death within months to a few years, whereas AMN usually progresses over decades. There remains no universal cure. Current care relies on newborn screening, repeated brain MRI surveillance, prompt steroid replacement for adrenal insufficiency, supportive neurological care, and—when early inflammatory brain lesions appear—an allogeneic hematopoietic stem-cell transplant (HSCT) from a donor or, for a narrowly defined group in the United States, autologous lentiviral gene therapy with elivaldogene autotemcel (Skysona). GeneReviews: X-Linked Adrenoleukodystrophy FDA: Skysona

Scope of Recent Research (2020–present)

Research activity has intensified around two related goals: preventing the inflammatory brain phase before irreversible damage occurs, and treating the spinal-cord and adrenal manifestations that HSCT does not reliably reverse. The field has produced a clinically available gene-addition therapy and several credible experimental approaches—including direct central-nervous-system gene delivery, CRISPR-based editing, and neuroprotective small molecules—but none yet restores normal ABCD1 function safely across all relevant tissues or constitutes a cure for every person with X-ALD. Lentiviral gene therapy for cALD GeneReviews: X-Linked Adrenoleukodystrophy

Major Breakthroughs and Emerging Therapies

The clearest clinical advance has been ex vivo lentiviral gene addition. In this procedure, clinicians collect a patient’s own blood-forming CD34+ stem cells, insert a working ABCD1 copy with the Lenti-D lentiviral vector, give chemotherapy to make space in the bone marrow, and reinfuse the corrected cells. The cells can generate brain-resident microglia-like cells over time, potentially limiting cerebral inflammation without requiring a donor or risking graft-versus-host disease. In the pivotal 32-patient study of early cALD, 29 patients (91%) were alive without major functional disability at 24 months; at a median follow-up of about six years, 26 patients (81%) remained free of major functional disability. Lentiviral gene therapy for cALD

That benefit does not eliminate major safety concerns. Skysona is FDA-approved only for boys aged 4–17 years with early, active cALD who lack an HLA-matched donor for allogeneic HSCT. In August 2025, the FDA strengthened its boxed warning after hematologic malignancies, including myelodysplastic syndrome and acute myeloid leukemia, had been reported in 10 of 67 clinical-trial recipients by July 2025. The risk is thought to relate to insertion of the integrating viral vector near cancer-related genes, so long-term blood monitoring is required. FDA: Skysona FDA safety labeling update

Direct gene delivery to the nervous system is being pursued particularly for AMN, for which marrow-based treatment is not established. SwanBio’s SBT101 uses an adeno-associated virus serotype 9 (AAV9) vector carrying ABCD1, administered into cerebrospinal fluid to deliver the gene to cells of the brain and spinal cord. This approach aims to treat the long spinal-cord pathways damaged in AMN while avoiding the need for myeloablative chemotherapy, but it remains an early-stage investigational therapy. SBT101 AMN trial

Gene editing remains preclinical but has advanced from corrected patient cells to animal studies. A 2022 study used CRISPR-based homology-independent targeted integration (HITI) to add a normal ABCD1 sequence in patient-derived fibroblasts and in Abcd1-deficient mice; systemic AAV9 delivery increased ABCD1 messenger RNA and reduced plasma C24:0- and C26:0-lysophosphatidylcholine biomarkers. A 2024 humanized-mouse study used adenine base editing to directly correct an ABCD1 disease variant, detecting editing in brain, spinal cord, and adrenal tissue alongside reduced very-long-chain-fatty-acid ratios. These results are encouraging proof-of-concept, not evidence of human safety or efficacy. HITI gene editing in ALD models Adenine base editing in a humanized ALD mouse

Small-molecule neuroprotection is represented by leriglitazone, an oral, brain-penetrant activator of peroxisome proliferator-activated receptor-gamma (PPARγ), a regulator of metabolism, mitochondrial function, and inflammation. In the randomized ADVANCE phase 2/3 AMN trial, leriglitazone did not improve the primary outcome—the 96-week change in six-minute walking distance—but fewer participants developed progressive cerebral disease in the treatment group than in the placebo group, supporting continued study in cALD. ADVANCE leriglitazone trial

Clinical Trials and Experimental Approaches

The completed phase 2/3 ALD-102 program of elivaldogene autotemcel, with ongoing long-term follow-up, is the most mature gene-therapy evidence base. The published 2024 analysis found 94% overall survival at 24 months and 91% of participants without major functional disability at that point; the trial also documented one case of myelodysplastic syndrome at month 92, illustrating why efficacy must be weighed against delayed genotoxicity. Lentiviral gene therapy for cALD

For pharmacological treatment, Minoryx Therapeutics’ NEXUS phase 2/3 study evaluated leriglitazone in boys aged 2–12 years with cALD. In the prespecified 24-week interim analysis, all 11 evaluable participants met the trial’s continuation criterion for decelerated lesion growth or disease arrest, five met both clinical and radiological criteria for disease arrest, and no treatment-related serious adverse events were reported. Because the study was open-label, small, and compared with natural-history expectations rather than a concurrent placebo group, the findings require cautious interpretation and durable follow-up. NEXUS interim analysis A separate randomized phase 3 CALYX trial is testing leriglitazone against placebo in approximately 40 adult men with cALD, with death or becoming bedridden with permanent ventilatory support as its primary endpoint. CALYX trial

For adult AMN, SwanBio’s SBT101 study is a phase 1/2 randomized, blinded, dose-escalation trial of intrathecal AAV9-ABCD1 gene therapy. It is designed principally to establish safety, dose, and biological activity; no peer-reviewed clinical efficacy results were identified for this report. SBT101 AMN trial

Methodologies and Scientific Approaches

Researchers use multiple complementary models because X-ALD affects several organs and has variable clinical courses even among people with the same genetic variant. These include patient fibroblasts, induced pluripotent stem cells, inflammatory and demyelination models, Abcd1-knockout rodents, and newer humanized mice carrying a specific human ABCD1 mutation. These systems allow investigators to measure restoration of ALD protein, correction of fatty-acid metabolism, myelin integrity, neuroinflammation, motor behavior, and editing accuracy before moving toward human studies. HITI gene editing in ALD models Adenine base editing in a humanized ALD mouse

Brain MRI remains central for identifying active cerebral disease early enough for intervention. Trials increasingly combine MRI measures—such as lesion volume, the Loes score, and gadolinium enhancement—with blood biomarkers including neurofilament light chain, which reflects nerve-cell injury, and C26:0-lysophosphatidylcholine, which reflects disturbed very-long-chain-fatty-acid metabolism. These tools are intended to make small rare-disease trials more informative and to detect treatment effects before major disability develops. NEXUS interim analysis GeneReviews: X-Linked Adrenoleukodystrophy

Leading Institutions and Funding

Major clinical and translational contributors include Massachusetts General Hospital and Harvard Medical School, Kennedy Krieger Institute and Johns Hopkins, the University of Minnesota, Amsterdam UMC, University Hospital Leipzig, Hospital Sant Joan de Déu, and leukodystrophy centers in France, Italy, Spain, and the United Kingdom. Bluebird bio developed elivaldogene autotemcel; Minoryx Therapeutics developed leriglitazone; and SwanBio is developing SBT101. Lentiviral gene therapy for cALD ADVANCE leriglitazone trial NEXUS interim analysis

In the United States, the NIH-funded Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN), supported through grant U54NS115052, provides infrastructure for natural-history studies, standardized assessments, trial readiness, and collaboration across leukodystrophies including ALD. This kind of network funding is especially important in a rare disease where individual centers cannot easily recruit or follow sufficiently large patient groups alone. NIH RePORTER: GLIA-CTN

Strengths, Limitations, and Challenges

The field’s core strength is that intervening early in inflammatory cALD can meaningfully preserve function, and gene addition has shown that restoring ABCD1 in a patient’s own hematopoietic stem cells can alter the clinical course. Newborn screening and serial MRI surveillance create a practical window in which treatment can occur before extensive brain injury. The major limitation is that current effective interventions are preventative rather than restorative: neither HSCT nor gene therapy reliably repairs established neurologic loss, and neither is established as a treatment for the broader AMN population. GeneReviews: X-Linked Adrenoleukodystrophy Lentiviral gene therapy for cALD

Safety, access, and biology remain difficult obstacles. Lentiviral gene therapy entails intensive chemotherapy and a documented delayed cancer risk, while allogeneic HSCT requires a suitable donor and carries graft-related risks. A case report also described secondary failure of lentiviral gene therapy in a boy with a whole-ABCD1 deletion, possibly associated with an immune response to newly expressed ALD protein; this finding needs confirmation but underscores that genotype-specific risks may matter. AAV and gene-editing approaches must still demonstrate sufficiently broad delivery to brain, spinal cord, and adrenal tissues, durable expression or editing, and acceptably low off-target and immune risks. FDA safety labeling update Secondary failure after lentiviral gene therapy

Outlook and Future Directions

As of September 7, 2026, X-ALD is closer to disease-modifying treatment than to a single, durable, body-wide cure. The most important milestones to watch are long-term safety and confirmatory-benefit data for Skysona; full, controlled evidence for leriglitazone in childhood and adult cALD; first human safety and biomarker data from intrathecal AAV9-ABCD1 therapy for AMN; and replication of in vivo editing results in larger, more clinically representative models. A true cure will likely require a therapy that safely corrects or compensates for ABCD1 across the nervous system and adrenal glands early enough to prevent inflammatory demyelination, while avoiding the cancer, immune, and delivery problems that currently constrain gene-based treatments. FDA: Skysona Adenine base editing in a humanized ALD mouse SBT101 AMN trial

References

• GeneReviews: X-Linked Adrenoleukodystrophy — Raymond, Moser, and Fatemi; University of Washington, updated 2023.
• FDA: Skysona — U.S. Food and Drug Administration, 2025.
• Lentiviral gene therapy for cALD — Eichler et al.; New England Journal of Medicine, 2024.
• FDA safety labeling update — U.S. Food and Drug Administration, 2025.
• SBT101 AMN trial — SwanBio Therapeutics; ClinicalTrials.gov, accessed 2026.
• HITI gene editing in ALD models — Hong et al.; Molecular Therapy, 2022.
• Adenine base editing in a humanized ALD mouse — Gopalappa et al.; Molecular Therapy, 2024.
• ADVANCE leriglitazone trial — Köhler et al.; The Lancet Neurology, 2023.
• NEXUS interim analysis — García-Cazorla et al.; eClinicalMedicine, 2025.
• CALYX trial — Minoryx Therapeutics; ClinicalTrials.gov, accessed 2026.
• NIH RePORTER: GLIA-CTN — National Institute of Neurological Disorders and Stroke, 2024.
• Secondary failure after lentiviral gene therapy — Lund et al.; Molecular Therapy, 2024.