Adrenoleukodystrophy

Overview

Adrenoleukodystrophy (ALD), usually X-linked adrenoleukodystrophy, is an inherited disorder caused by harmful variants in the ABCD1 gene. The resulting shortage of the ALD protein disrupts breakdown of very-long-chain fatty acids (VLCFAs), which then accumulate in tissues. ALD can cause adrenal failure, a slowly worsening spinal-cord and peripheral-nerve disorder called adrenomyeloneuropathy (AMN), and—in some boys and men—a rapidly destructive inflammatory brain disease called cerebral ALD (CALD). Boys and men are most severely affected, but many women with an ABCD1 variant develop later-life myeloneuropathy as well. International ALD recommendations

Prognosis differs sharply by form. Untreated active childhood CALD can rapidly lead to severe disability or death, whereas AMN usually progresses over years with stiffness, walking impairment, pain, and bladder or bowel problems. Current care combines regular brain MRI and adrenal monitoring, steroid replacement for adrenal insufficiency, rehabilitation and symptom treatment for AMN, and rapid referral for hematopoietic cell transplantation (HCT) when early active CALD is detected. HCT can halt early cerebral inflammation but does not reliably reverse established neurologic injury or treat spinal-cord disease and adrenal insufficiency. International ALD recommendations

Scope of Recent Research (2020–present)

Research since 2020 has been active but concentrated in a few high-stakes areas: improving early detection of CALD, making stem-cell treatment safer, developing therapies for AMN and women with ALD, and attempting permanent ABCD1 repair. The field has achieved an important disease-modifying advance—autologous lentiviral gene therapy for selected boys with early active CALD—but it is not yet close to a universal cure because available interventions do not address every ALD phenotype, require treatment before extensive brain damage, and carry substantial safety and delivery challenges. SKYSONA prescribing information International ALD recommendations

Major Breakthroughs and Emerging Therapies

The principal clinical breakthrough is ex vivo lentiviral gene therapy with elivaldogene autotemcel, or eli-cel (Skysona). Doctors collect a patient’s own blood-forming CD34-positive stem cells, add a working ABCD1 copy using the Lenti-D lentiviral vector, give chemotherapy to clear marrow space, and infuse the corrected cells back into the patient. In a phase 2–3 study of 32 boys with early, active CALD, 29 reached the 24-month assessment without major functional disabilities; overall survival at 24 months was 94%. At a median follow-up of six years, 30 of 32 had stable neurologic-function scores and 26 remained free of major functional disability. Lentiviral gene therapy for CALD

This strategy avoids donor matching and graft-versus-host disease, but it is not a risk-free “one-time cure.” Because lentiviral DNA integrates into the recipient’s genome, insertional oncogenesis—cancer caused in part by vector integration—remains a central concern. The pivotal study reported myelodysplastic syndrome in one patient at month 92, and the FDA subsequently strengthened Skysona’s boxed warning after additional reports of myelodysplastic syndrome and acute myeloid leukemia. The current U.S. indication is limited to boys aged 4–17 years with early active CALD who lack an available HLA-matched donor for allogeneic HCT. Lentiviral gene therapy for CALD FDA Skysona safety update SKYSONA prescribing information

Researchers are also testing ways to deliver ABCD1 correction more directly to the nervous system. A 2024 single-arm phase I study reported multisite intracerebral injection of an ABCD1-carrying lentiviral vector in children with CALD; this approach is experimental and primarily evaluates feasibility and safety rather than proving durable clinical benefit. Intracerebral lentiviral-ABCD1 phase I trial In parallel, preclinical teams are pursuing CRISPR-based editing. Homology-independent targeted integration (HITI) increased ABCD1 expression and lowered plasma VLCFA markers in Abcd1-knockout mice after dual AAV9-vector delivery. AAV-HITI gene editing study A newer study used adenine base editing to correct a specific human ABCD1 mutation in patient-derived cells and, in a humanized mouse model, reduced plasma VLCFAs after systemic dual-AAV treatment. Adenine base editing in humanized ALD mice These are important proofs of concept, but neither editing approach has entered human ALD trials.

Small-molecule approaches aim to reduce inflammation, improve cellular energy handling, or compensate for the missing ALD transporter. Leriglitazone, an oral PPAR-gamma agonist, did not meet the primary walking-distance endpoint in the 96-week randomized phase 2–3 ADVANCE trial in men with AMN. However, clinically progressive CALD occurred in six participants, all assigned to placebo, supporting further study of its possible effect on cerebral conversion. ADVANCE leriglitazone trial An uncontrolled 2024 report in 13 adults with early CALD found clinical and MRI stabilization in 10 participants during up to two years of follow-up, but this small observational result cannot establish that leriglitazone substitutes for transplant. Leriglitazone in adult CALD Other laboratory programs include brain-penetrant thyroid-hormone mimetics such as Sob-AM2, which reduced CNS VLCFAs more effectively than sobetirome in Abcd1-deficient mice, and antisense oligonucleotides designed to activate the related ABCD2 gene as a functional backup transporter. Sob-AM2 mouse study Kennedy Krieger ALD research update

Clinical Trials and Experimental Approaches

The best-developed recent program is eli-cel. The completed ALD-102 phase 2–3 study and its long-term follow-up generated the main efficacy dataset, while ALD-104 is a phase 3 study of eli-cel after busulfan/fludarabine conditioning in children aged 17 years or younger with CALD. Lentiviral gene therapy for CALD ALD-104 phase 3 protocol FDA approval was accelerated, based on 24-month survival without major functional disability, and continued approval depends on confirmatory evidence of clinical benefit. SKYSONA prescribing information

Minoryx Therapeutics sponsored the completed phase 2–3 ADVANCE trial of leriglitazone in 116 ambulatory men with AMN; the study’s primary endpoint was not met, despite the intriguing imbalance in cerebral ALD events. ADVANCE leriglitazone trial The registered study record lists primary completion in June 2021, final completion in March 2025, and an open-label extension component. ADVANCE ClinicalTrials.gov record Direct intracerebral lentiviral ABCD1 administration remains at phase I, while CRISPR/HITI and base-editing strategies remain preclinical. Intracerebral lentiviral-ABCD1 phase I trial AAV-HITI gene editing study Adenine base editing in humanized ALD mice

Methodologies and Scientific Approaches

ALD research combines natural-history cohorts, newborn screening, serial contrast-enhanced MRI, standardized neurologic measures, and biochemical biomarkers. In CALD, MRI lesion burden and enhancement identify active inflammatory disease early enough for HCT or gene therapy; trials also track neurologic-function scores and survival without major functional disabilities. In AMN, investigators are seeking more sensitive measures than conventional walking tests, including wearable gait and balance measures, quantitative brain and spinal MRI, plasma neurofilament light chain, and VLCFA-related metabolites such as C26:0-lysophosphatidylcholine. International ALD recommendations Leriglitazone in adult CALD Kennedy Krieger ALD research update

Researchers also use patient fibroblasts, induced pluripotent stem cells, and three-dimensional brain and spinal-cord organoids to test cell-specific consequences of ABCD1 loss and candidate therapies. A 2025 organoid study found elevated VLCFAs and reduced brain-relevant lipids, including sulfatides and gangliosides, in ALD cortical organoids. ALD cortical and spinal organoids These human models complement mice, whose biochemical abnormalities are useful but often fail to reproduce the aggressive inflammatory cerebral disease seen in people. Adenine base editing in humanized ALD mice

Leading Institutions and Funding

Major clinical and translational contributors include Massachusetts General Hospital and Harvard Medical School, Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, the University of Minnesota, Kennedy Krieger Institute and Johns Hopkins, Amsterdam UMC, University College London/Great Ormond Street Hospital, and European CALD and AMN centers that participated in gene-therapy and leriglitazone studies. Bluebird bio developed and sponsored eli-cel, while Minoryx Therapeutics sponsored ADVANCE. Lentiviral gene therapy for CALD ADVANCE leriglitazone trial

Patient-led infrastructure is increasingly important. ALD Connect reports an $800,000 Chan Zuckerberg Initiative grant and a $1 million pledge for its Breakthrough Research Fund and Collaborative Research Network. ALD Connect impact report ALD Connect Collaborative Research Network Federal support includes a 2026 NIH/NINDS R21 award of $445,500 to the Hugo W. Moser Research Institute at Kennedy Krieger for testing whether cystic-fibrosis transporter modulators can restore function in selected ALD-associated ABCD1 missense variants. NIH/NINDS ALD drug-repurposing award

Strengths, Limitations, and Challenges

The field’s major strength is that early CALD is now actionable: MRI surveillance can identify inflammatory lesions before severe irreversible deficits, and allogeneic HCT or autologous gene-corrected stem cells can stabilize many appropriately selected patients. International ALD recommendations Lentiviral gene therapy for CALD Autologous therapy solves the donor-matching and graft-versus-host-disease problems of allogeneic HCT, but it still requires intensive conditioning chemotherapy, specialized manufacturing, long-term follow-up, and lifelong monitoring for blood cancers. FDA Skysona safety update

The central limitation is incomplete coverage of the disease. Skysona is not approved to prevent or treat ALD-related adrenal insufficiency, and neither HCT nor gene therapy has established benefit for the chronic spinal-cord disease of AMN or for symptomatic women. SKYSONA prescribing information International ALD recommendations Important open questions include why people with the same ABCD1 variant develop different phenotypes, how to predict cerebral conversion, how to reach brain, spinal cord, and adrenal tissue safely with genetic medicines, and whether edited or vector-treated cells will remain effective for decades. A reported secondary failure of eli-cel in a boy with a whole-gene ABCD1 deletion, apparently associated with loss of vector-marked cells and an immune response to newly expressed ALD protein, illustrates the need for genotype-specific vigilance. Secondary failure after eli-cel

Outlook and Future Directions

As of October 7, 2026, ALD has no single therapy that permanently corrects every manifestation for every patient. The nearest practical goal is safer, earlier, and more durable prevention of neurologic decline in CALD, alongside the first validated disease-modifying treatment for AMN and symptomatic women. Milestones to watch are long-term eli-cel cancer and durability data, completion of required postmarketing safety follow-up, replication of leriglitazone’s cerebral-disease signals in controlled studies, better predictive biomarkers, and translation of ABCD1 gene editing from patient cells and mice into rigorously monitored human trials. FDA Skysona safety update Adenine base editing in humanized ALD mice ALD Connect Collaborative Research Network

References

• International recommendations for the diagnosis and management of patients with adrenoleukodystrophy — Engelen et al., Neurology, 2022.
• Lentiviral gene therapy for cerebral adrenoleukodystrophy — Eichler et al., New England Journal of Medicine, 2024.
• SKYSONA prescribing information — U.S. Food and Drug Administration, 2025.
• FDA investigation of hematologic malignancy risk following Skysona — U.S. Food and Drug Administration, 2024.
• ALD-104 phase 3 protocol — ClinicalTrials.gov and bluebird bio, 2022.
• ADVANCE leriglitazone trial — Köhler et al., The Lancet Neurology, 2023.
• ADVANCE ClinicalTrials.gov record — U.S. National Library of Medicine, 2025.
• Leriglitazone in adult CALD — Golse et al., Brain, 2024.
• Intracerebral lentiviral-ABCD1 phase I trial — Wang et al., Science Bulletin, 2024.
• AAV-HITI gene editing study — Hong et al., Molecular Therapy, 2022.
• Adenine base editing in humanized ALD mice — Seo et al., Molecular Therapy, 2024.
• Sob-AM2 mouse study — Weiner et al., Cell Chemical Biology, 2020.
• Kennedy Krieger ALD research update — Kennedy Krieger Institute, 2023.
• ALD cortical and spinal organoids — Fernández et al., iScience, 2025.
• Secondary failure after eli-cel — Lund et al., Molecular Therapy, 2024.
• ALD Connect impact report — ALD Connect, 2026.
• ALD Connect Collaborative Research Network — ALD Connect, 2026.
• NIH/NINDS ALD drug-repurposing award — U.S. Department of Health and Human Services, 2026.