Intrathecal Adeno-Associated Viral Vector-Mediated Gene Delivery for Adrenomyeloneuropathy
Open accessAbstract
Mutations in the gene encoding the peroxisomal ATP-binding cassette transporter (ABCD1) cause elevations in very long-chain fatty acids (VLCFAs) and the neurodegenerative disease adrenoleukodystrophy (ALD). In most adults, this manifests as the spinal cord axonopathy adrenomyeloneuropathy (AMN). A challenge in virus-based gene therapy in AMN is how to achieve functional gene correction to the entire spinal cord while minimizing leakage into the systemic circulation, which could contribute to toxicity. In the present study, we used an osmotic pump to deliver adeno-associated viral (AAV) vector into the lumbar cerebrospinal fluid space in mice. We report that slow intrathecal delivery of recombinant AAV serotype 9 (rAAV9) achieves efficient gene transfer across the spinal cord and dorsal root ganglia as demonstrated with two different transgenes, GFP and ABCD1. In the Abcd1–/– mouse, gene correction after continuous rAAV9-CBA-hABCD1 delivery led to a 20% decrease in VLCFA levels in spinal cord compared with controls. The major cell types transduced were astrocytes, vascular endothelial cells, and neurons. Importantly, rAAV9 delivered intrathecally by osmotic pump, in contrast to bolus injection, reduced systemic leakage into peripheral organs, particularly liver and heart tissue.
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Shortly after intrathecal injection of an AAV9-CBA-hABCD1 vector into 3-5-month Abcd1−/− mice, ALDP expression was found in spinal cord and DRG neurons, but not in OLs.
“Shortly after intrathecal injection of an AAV9–CBA–hABCD1 vector into 3–5-month Abcd1−/− mice, ALDP expression was found in spinal cord and DRG neurons, but not in OLs [290,291].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [290]
The cited routes of administration did not allow the vector to transduce neurons of the motor cortex from which corticospinal axons originate.
“In addition, the cited routes of administration did not allow the vector to transduce neurons of the motor cortex from which corticospinal axons originate.”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [290]
VLCFA accumulation was decreased by 9-24% in the spinal cord white matter after neuron-targeting gene therapy.
“VLCFA accumulation was decreased by 9–24% in the spinal cord white matter [79,290,306].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [290]
Restoration of ABCD1 expression of the neuron populations targeted in these studies had no significant or consistent effect on motor performance.
“In summary, restoration of ABCD1 expression of the neuron populations targeted in these studies had no significant or consistent effect on motor performance.”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [290]
The co-transduction of astrocytes may have played an additional role in the gene therapy effect.
“The co-transduction of astrocytes may have played an additional role, as suggested by previous gene therapy attempts that used a vector targeting neurons and astrocytes, but this had a more limited effect than the OL-targeting vector [79,290,291].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [290]
An AAV9-CBA-hABCD1 vector targeting neurons and/or astrocytes had only a partial effect on disease phenotypes, notably motor deficits.
“It was previously observed that an AAV9-CBA-hABCD1 vector targeting neurons and/or astrocytes had only a partial effect on disease phenotypes, notably the motor deficits [79,290,291].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [290]
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“Further testing in nonhuman primates may enable the development of intrathecal AAV9-ABCD1 as a gene therapy for AMN.”
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Gene therapy for the leukodystrophies: From preclinical animal studies to clinical trials.
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- Authors
- Gong, Y., Berenson, A., Laheji, F., Gao, G., Wang, D., Ng, C., Volak, A., Kok, R., Kreouzis, V., Dijkstra, I. M., Kemp, S., Maguire, C. A., & Eichler, F.
- Affiliations
- Harvard University (US)
- University of Massachusetts Chan Medical School (US)
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
- Amsterdam UMC Location University of Amsterdam (NL)
- Corresponding author
- Eichler, Florian
- ORCID
- Venue
- Human Gene Therapy
- Publisher
- SAGE Publications
- Published
- 2019-05
- Volume
- 30
- Issue
- 5
- Pages
- 544-555
- ISSN
- 1043-0342 (ISSN-L)
- 1557-7422
- PMC
- PMC6909708
- OpenAlex
- W2898100827
- Cited by
- 45
- References
- 9
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 13 · 2023: 6 · 2022: 4 · 2021: 3 · 2020: 6 · 2019: 3
- FWCI
- 1.84
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Human Gene Therapy (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion, other-oa)
- Funders
- National Heart, Lung, and Blood Institute (UG3HL147367)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Health Sciences › Medicine › Genetics › Neurogenetic and Muscular Disorders Research
- Keywords
- adrenomyeloneuropathy, adrenoleukodystrophy, ABCD1, AAV9, intrathecal gene delivery, osmotic pump, very long chain fatty acids, spinal cord, dorsal root ganglia, gene therapy
- MeSH terms
- ATP Binding Cassette Transporter, Subfamily D, Member 1, Dependovirus, Adrenoleukodystrophy, Animals, Astrocytes, Disease Models, Animal, Fibroblasts, Genetic Vectors, Humans, Injections, Spinal, Spinal Cord, Genetic Therapy, Gene Transfer Techniques, Cell Line, Tumor, Mice
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