An in vitro and in vivo efficacy evaluation of gene therapy candidate SBT101 in mouse models of adrenomyeloneuropathy and in NHPs
Open accessAbstract
Adrenomyeloneuropathy is a progressive neurodegenerative disease caused by pathogenic variants in the ABCD1 gene, resulting in very-long-chain fatty acid (VLCFA) accumulation that leads to dying-back axonopathy. Our candidate gene therapy, SBT101 (AAV9-human ABCD1 [h ABCD1 ]), aims to ameliorate pathology by delivering functional copies of h ABCD1 to the spinal cord. Transduced cells produce functional ABCD1 protein, thereby repairing the underlying biochemical defect. In vitro and in vivo mouse studies were conducted to assess the biochemical and functional efficacy of SBT101 and show effective delivery to target tissues involved in the disease pathology: spinal cord and dorsal root ganglia. Administration of SBT101 to mixed glial cell cultures from Abcd1 -Null mice, and to male Abcd1 knockout ( Abcd1 −/y ) and double-knockout ( Abcd1 −/y / Abcd2 −/− ) mice led to increased hABCD1 production and reduced VLCFA. Double-knockout mice also exhibited improved grip strength. Furthermore, we conducted biodistribution and safety assessments in nonhuman primates. Six-hour intrathecal lumbar infusions demonstrated effective transduction throughout target tissues, supporting the clinical feasibility of the procedure. SBT101 was well tolerated, with no observed SBT101-related mortality or clinical signs. These findings not only provide preclinical efficacy data for SBT101 but also inform clinically relevant SBT101 dose selection for patients with adrenomyeloneuropathy.
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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 [306]
The Results (SBT101 in Abcd1−/y mice; page unavailable) report significant VLCFA reductions in spinal cord tissue at 13 and 24 weeks after SBT101 treatment. The paper does not give a 9–24% reduction or identify the measured tissue as spinal cord white matter; it also reports hABCD1 expression in both neurons and astrocytes. (LLM, conf=0.87)
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- Authors
- Vasireddy, V., Maguire, C. A., Anderson, D. W., Ng, C., Gong, Y., Eichler, F., Fourcade, S., Guilera, C., Onieva, A., Sanchez, A., Leal-Julià, M., Verdés, S., Dijkstra, I. M. E., Kemp, S., Park, H., Lutz, T., Clark, S. W., Bosch, A., Pujol, A., & Kozarsky, K.
- Affiliations
- Harvard University (US)
- Instituto de Salud Carlos III (ES)
- Universitat Autònoma de Barcelona (ES)
- Amsterdam UMC Location University of Amsterdam (NL)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Corresponding author
- Kozarsky, Karen
- ORCID
- Venue
- Molecular Therapy - Methods & Clinical Development
- Publisher
- Elsevier BV
- Published
- 2024-12
- Volume
- 32
- Issue
- 4
- Pages
- 101354
- ISSN
- 2329-0501 (ISSN-L)
- PMC
- PMC11550353
- OpenAlex
- W4403270594
- Cited by
- 6
- References
- 42
- Citations by year
- 2026: 2 · 2025: 4
- FWCI
- 1.59
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Therapy — Methods & Clinical Development (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Dipòsit Digital de Documents de la UAB (Universitat Autònoma de Barcelona) (submittedVersion, cc-by-nc-nd)
- 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, gene therapy, ABCD1, very long chain fatty acids, intrathecal gene delivery, non-human primates, tissue distribution, safety, grip strength, double knockout mice, dose selection
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