Enzyme, cell and gene‐based therapies for metachromatic leukodystrophy
Abstract
Summary: Metachromatic leukodystrophy (MLD) is a demyelinating storage disease caused by deficiency of the lysosomal enzyme arylsulfatase A (ARSA). Lack of ARSA activity leads to the accumulation of galactosylceramide‐3‐O‐sulfate (sulfatide) in the central and peripheral nervous systems. Based on the age at onset, the disease is usually classified into three forms: the late‐infantile form, which manifests in the second year of life; the juvenile variants (onset between 4 and 12 years), which are subdivided into early‐juvenile (EJ, onset before 6 years) and late‐juvenile (LJ, onset after 6 years); and the adult form (onset after 12 years of age). Currently, there is no efficient therapy for the late‐infantile form of MLD (50% of the patients), death occurring within a few years after onset of neurological symptoms. Allogeneic haematopoietic cell transplantation (HCT), when performed at a very early stage of the disease, may improve selected patients with juvenile or adult forms of MLD. As with other lysosomal storage diseases, the physiopathology of MLD is poorly understood. Demyelination is the main pathological finding, but substantial storage of sulfatides in neurons also occurs, and may contribute to the clinical phenotype. The physiopathological process leading to neuronal and glial cell degeneration and apoptosis involves accumulation of undegraded sulfatides but also secondary abnormalities (storage/mislocalization of unrelated lipids, inflammatory processes). This review summarizes the recent advances in the understanding of the physiopathology of MLD and the new therapeutic perspectives currently under preclinical investigation, including enzyme replacement therapy, gene therapy and cell therapy.
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AAV vector administration to the CNS has an excellent safety and efficacy profile.
“AAV vector administration to the CNS has an excellent safety and efficacy profile.”
From AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease (2018) · cites this paper as [60]
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- Authors
- Sevin, C., Aubourg, P., & Cartier, N.
- Affiliations
- Inserm (FR)
- Corresponding author
- Cartier, N.
- ORCID
- Venue
- Journal of Inherited Metabolic Disease
- Publisher
- Wiley
- Published
- 2007-03-08
- Volume
- 30
- Issue
- 2
- Pages
- 175-183
- ISSN
- 0141-8955 (ISSN-L)
- 1573-2665
- OpenAlex
- W2158767137
- Cited by
- 88
- References
- 84
- Citations by year
- 2025: 4 · 2024: 2 · 2023: 5 · 2022: 7 · 2021: 5 · 2020: 4 · 2019: 2 · 2018: 3 · 2017: 4 · 2016: 6 · 2015: 3 · 2014: 5 · 2013: 4 · 2012: 5
- FWCI
- 0.83
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Inherited Metabolic Disease (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Fondation pour la Recherche Médicale
- Topics
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
- Keywords
- metachromatic leukodystrophy, sulfatide accumulation, demyelination, lysosomal storage disease, late infantile MLD, allogeneic haematopoietic cell transplantation, enzyme replacement therapy, gene therapy, cell therapy, pathophysiology, neuronal apoptosis
- MeSH terms
- Animals, Disease Models, Animal, Enzymes, Humans, Leukodystrophy, Metachromatic, Genetic Therapy, Stem Cell Transplantation, Enzyme Therapy
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