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Enzyme, cell and gene-based therapies for metachromatic leukodystrophy

  • ICIEM 2006
  • Published:
Journal of Inherited Metabolic Disease

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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Abbreviations

AAV:

adeno-associated virus

ARSA:

arylsulfatase A

CNS:

central nervous system

EJ:

early juvenile

ERT:

enzyme replacement therapy

ES:

embryonic stem

FGE:

Cα-formylglycine generating enzyme

GalCer:

galactosylceramide

GFP:

green fluorescent protein

HCT:

haematopoietic cell transplantation

HSC:

haematopoietic stem cell

LI:

late infantile

LJ:

late juvenile

LSD:

lysosomal storage disease

MAL:

myelin and lymphocyte protein

MLD:

metachromatic leukodystrophy

MSC:

mesenchymal stem cell

OLP:

oligodendroglial progenitor

PNS:

peripheral nervous system

Sulf:

sulfatide

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Authors and Affiliations

  1. University René-Descartes Paris 5, INSERM U745, Paris, France

    C. Sevin, P. Aubourg & N. Cartier

  2. Department of Pediatric Neurology, Hôpital Saint-Vincent de Paul, 82 avenue Denfert-Rochereau, 75014, Paris, France

    C. Sevin, P. Aubourg & N. Cartier

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  1. C. Sevin
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  2. P. Aubourg
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  3. N. Cartier
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Correspondence to N. Cartier.

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Communicating editor: Verena Peters

Competing interests: None declared

References to electronic databases: Arylsulfatase A (EC 3.1.6.8)

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Sevin, C., Aubourg, P. & Cartier, N. Enzyme, cell and gene-based therapies for metachromatic leukodystrophy. J Inherit Metab Dis 30, 175–183 (2007). https://doi.org/10.1007/s10545-007-0540-z

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