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Review

An AAV-Based Therapy Approach for Neurological Phenotypes of X-Linked Adrenoleukodystrophy

by
Ekaterina Gornostal
1,2,†,
Almaqdad Alsalloum
1,2,†,
Egor Degtyarev
1,2,
Ekaterina Kuznetsova
1,2,
Aygun Levashova
1,2,
Daria Mishina
1,2,
Natalia Mingaleva
1,2,
Ali Mazloum
1,2,
Viktor Bogdanov
1,2,
Julia Krupinova
1,2,3,
Sergey Mikhalkov
2,
Irina Rybkina
4,
Olga Mityaeva
1,5 and
Pavel Volchkov
1,3,5,*
1
Federal State Budgetary Scientific Institution “Federal Research Center for Innovator and Emerging Biomedical and Pharmaceutical Technologies”, 125315 Moscow, Russia
2
Moscow Center for Advanced Studies, Kulakova Str. 20, 123592 Moscow, Russia
3
Loginov Moscow Clinical Scientific Center, 111123 Moscow, Russia
4
Department of Endocrinology, Morozov Children’s Clinical Hospital, 119049 Moscow, Russia
5
Department of Fundamental Medicine, Lomonosov Moscow State University, 119992 Moscow, Russia
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2025, 26(23), 11645; https://doi.org/10.3390/ijms262311645
Submission received: 12 October 2025 / Revised: 19 November 2025 / Accepted: 24 November 2025 / Published: 1 December 2025
(This article belongs to the Special Issue Neurodegenerative Disease: From Molecular Basis to Therapy, 4th Edition)
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Abstract

X-linked adrenoleukodystrophy (X-ALD) is a monogenic progressive neurodegenerative disorder, being simultaneously a systemic metabolic disease and demonstrating severe neurological manifestations with effects to the brain and spinal cord. The objective of the current review is to provide a detailed approach to adeno-associated virus (AAV)-based gene therapy for neurological manifestations of X-ALD. The development of a successful AAV-mediated gene therapy hinges on its ability to deliver ABCD1 cDNA effectively to the relevant organs and cell types, induce therapeutic levels of protein expression, and ultimately, restore normal very-long chain fatty acids (VLCFA) metabolic function. Thus, several key considerations should be addressed when designing AAV-based gene therapy for X-ALD, including the genetic background of the disease and requisite transgene expression levels, the biochemical function of the adrenoleukodystrophy protein (ALDP), the identification of target cells and their role in pathogenesis, the regulation of expression within the genetic construct, the route of administration, the selection of an AAV serotype with high tropism for the central and peripheral nervous systems, and the development of robust in vitro and in vivo models.
Keywords: X-linked adrenoleukodystrophy; X-ALD; demyelinating disorders; AAV; gene therapy X-linked adrenoleukodystrophy; X-ALD; demyelinating disorders; AAV; gene therapy

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MDPI and ACS Style

Gornostal, E.; Alsalloum, A.; Degtyarev, E.; Kuznetsova, E.; Levashova, A.; Mishina, D.; Mingaleva, N.; Mazloum, A.; Bogdanov, V.; Krupinova, J.; et al. An AAV-Based Therapy Approach for Neurological Phenotypes of X-Linked Adrenoleukodystrophy. Int. J. Mol. Sci. 2025, 26, 11645. https://doi.org/10.3390/ijms262311645

AMA Style

Gornostal E, Alsalloum A, Degtyarev E, Kuznetsova E, Levashova A, Mishina D, Mingaleva N, Mazloum A, Bogdanov V, Krupinova J, et al. An AAV-Based Therapy Approach for Neurological Phenotypes of X-Linked Adrenoleukodystrophy. International Journal of Molecular Sciences. 2025; 26(23):11645. https://doi.org/10.3390/ijms262311645

Chicago/Turabian Style

Gornostal, Ekaterina, Almaqdad Alsalloum, Egor Degtyarev, Ekaterina Kuznetsova, Aygun Levashova, Daria Mishina, Natalia Mingaleva, Ali Mazloum, Viktor Bogdanov, Julia Krupinova, and et al. 2025. "An AAV-Based Therapy Approach for Neurological Phenotypes of X-Linked Adrenoleukodystrophy" International Journal of Molecular Sciences 26, no. 23: 11645. https://doi.org/10.3390/ijms262311645

APA Style

Gornostal, E., Alsalloum, A., Degtyarev, E., Kuznetsova, E., Levashova, A., Mishina, D., Mingaleva, N., Mazloum, A., Bogdanov, V., Krupinova, J., Mikhalkov, S., Rybkina, I., Mityaeva, O., & Volchkov, P. (2025). An AAV-Based Therapy Approach for Neurological Phenotypes of X-Linked Adrenoleukodystrophy. International Journal of Molecular Sciences, 26(23), 11645. https://doi.org/10.3390/ijms262311645

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