Journal of Inherited Metabolic Disease

, Volume 30, Issue 2, pp 175–183

Enzyme, cell and gene-based therapies for metachromatic leukodystrophy

ICIEM 2006

DOI: 10.1007/s10545-007-0540-z

Cite this article as:
Sevin, C., Aubourg, P. & Cartier, N. J Inherit Metab Dis (2007) 30: 175. doi:10.1007/s10545-007-0540-z

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.

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

Copyright information

© SSIEM and Springer 2007

Authors and Affiliations

  1. 1.University René-Descartes Paris 5, INSERM U745ParisFrance
  2. 2.Department of Pediatric NeurologyHôpital Saint-Vincent de PaulParisFrance