Intracisternal AAV9-MAG- hABCD1 Vector Reverses Motor Deficits in Adult Adrenomyeloneuropathy Mice
Abstract
Worldwide, thousands of male patients who carry ATP Binding Cassette Subfamily D Member 1 ( ABCD1 ) mutations develop adrenomyeloneuropathy (AMN) in mid-adulthood, a debilitating axonopathy of the spinal cord. Today AAV gene therapy brings the most hope for this orphan disease. We previously reported that an AAV9-MAG- hABCD1 vector injected intravenously in the neonatal period prevented the disease in 2-year-old Abcd1−/− mice, the AMN mouse model. In the current study, the same vector was injected intracisternally at 18 months of age, when about half of Abcd1−/− mice start losing balance and motricity. As soon as 1–3 months after vector injection, motor tests have evolved differently in treated and untreated (UT) mice. Six months after vector, treated mice ( n = 24) had near-normal motor performances, whereas neurological state had deteriorated in UT mice ( n = 34). In five white matter regions of the cervical spinal cord, hABCD1 expression at 24 months of age was present in 22% (18–27) of oligodendrocytes (OLs) and 22% (17–26) of astrocytes and not detected in neurons or microglia. Abundant hABCD1 expression was also observed in OLs and astrocytes in the cerebellum and brainstem and, to a lesser level, in the lower spinal cord, not in the dorsal root ganglia or brain cortex. In conclusion, the effect of the AAV9-MAG- hABCD1 vector at an early symptomatic stage of the Abcd1−/− mouse model paves a new oligotropic way for the gene therapy of AMN.
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Motor performance remained normal in all 40 Abcd1−/− mice until 16 months of age.
“Motor performance remained normal in all mice until 16 months of age.”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [176]
OL and astrocyte counts were normal in the dorsal columns of the spinal cord, corpus callosum, and cerebellum of Abcd1−/− mice.
“OL and astrocyte counts were normal in the dorsal columns of the spinal cord, corpus callosum, and cerebellum [172,176].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [176]
The axonopathy of Abcd1−/− mice was largely functional.
“Based on the surprisingly rapid vector effect, we postulated that the axonopathy of these mice was largely functional [176]; indeed, allowing ABCD1 expression to be reinstalled in OL peroxisomes is likely to restore the function of crucial metabolic pathways [149].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [176]
As early as 1-3 months post-injection, treated mice had restored and near-normal motor performances, whereas untreated mice experienced neurological deterioration.
“As early as 1–3 months post-injection, the treated mice had restored and near-normal motor performances, whereas untreated mice experienced neurological deterioration.”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [176]
At 24 months of age, hABCD1 expression was present in 22% of white matter cervical spinal cord OLs and 22% of astrocytes.
“At 24 months of age, hABCD1 expression was present in 22% in the white matter cervical spinal cord OLs and 22% of astrocytes.”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [176]
No ABCD1 expression was detected in motor cortex or DRG neurons, parental somata of the corticospinal and spinocerebellar tracts, or in the spinal cord or brain microglia.
“No ABCD1 expression was detected in motor cortex or DRG neurons, parental somata of the corticospinal and spinocerebellar tracts, or in the spinal cord or brain microglia [176].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [176]
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“43 Microglia has been considered a potential target for gene therapy despite the absence of overt neuroin fl am-matory lesions in the spinal cord.”
Adenoassociated virus serotype 9-mediated gene therapy for x-linked adrenoleukodystrophy
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“16, 17 AMN is still an orphan disease.”
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“25 We previously observed that this vector intravenously injected into newborn Abcd1 - / - mice was able to transduce OLs and astrocytes and to prevent motor disorders until 2 years of age.”
Phenotypic heterogeneity of an adult form of adrenoleukodystrophy in monozygotic twins
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Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy
Bougnères, P., & Le Stunff, C. (2025) · Genes · doi:10.3390/genes16050590 · Cited by 11 · see citing works
- Authors
- Özgür Günes, Y., Le Stunff, C., & Bougnères, P.
- Affiliations
- Laboratoire des Maladies Neurodégénératives, MIRCen Institute, Fontenay-aux-Roses, France
- ORCID
- Bougnères, Pierre
- Venue
- Human Gene Therapy
- Publisher
- SAGE Publications
- Published
- 2025-02
- Volume
- 36
- Issue
- 3-4
- Pages
- 88-100
- ISSN
- 1043-0342 (ISSN-L)
- 1557-7422
- OpenAlex
- W4405802767
- Cited by
- 2
- References
- 11
- Citations by year
- 2025: 2
- FWCI
- 0.53
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Gene Therapy (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Agence Nationale de la Recherche (ANR-11-INBS-0011)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Health Sciences › Medicine › Genetics › Neurogenetic and Muscular Disorders Research
- Keywords
- adrenomyeloneuropathy, ABCD1 mutations, motor impairment, oligodendrocytes, astrocytes, cerebellum, brainstem
- MeSH terms
- ATP Binding Cassette Transporter, Subfamily D, Member 1, Dependovirus, Adrenoleukodystrophy, Animals, Disease Models, Animal, Genetic Vectors, Humans, Male, Oligodendroglia, Spinal Cord, Genetic Therapy, Mice, Knockout, Mice
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