Sevin, C, Verot, L, Benraiss, A, Van Dam, D, Bonnin, D, Nagels, G et al.. Partial cure of established disease in an animal model of metachromatic leukodystrophy after intracerebral adeno-associated virus-mediated gene transfer. Gene Ther 14: 405-414

University of Antwerp, Antwerpen, Flanders, Belgium
Gene Therapy (Impact Factor: 3.1). 04/2007; 14(5):405-14. DOI: 10.1038/
Source: PubMed


Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by genetic deficiency of arylsulfatase A (ARSA) enzyme. Failure in catalyzing the degradation of its major substrate, sulfatide (Sulf), in oligodendrocytes and Schwann cells leads to severe demyelination in the peripheral (PNS) and central nervous system (CNS), and early death of MLD patients. The ARSA knockout mice develop a disease that resembles MLD but is milder, without significant demyelination in the PNS and CNS. We showed that adeno-associated virus serotype 5-mediated gene transfer in the brain of ARSA knockout mice reverses Sulf storage and prevents neuropathological abnormalities and neuromotor disabilities when vector injections are performed at a pre-symptomatic stage of disease. Direct injection of viral particles into the brain of ARSA knockout mice at a symptomatic stage results in sustained expression of ARSA, prevention of Sulf storage and neuropathological abnormalities. Despite these significant corrections, the treated mice continue to develop neuromotor disability. We show that more subtle biochemical abnormalities involving gangliosides and galactocerebroside are in fact not corrected.

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Available from: Debby Van Dam, Mar 06, 2014
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    • "By contrast, SC-mediated cellular repair in the CNS mainly acts to stimulate endogenous cells to respond to injury and trigger regenerative processes (Papastefanaki et al. 2007; Lavdas et al. 2010). While mammalian viral vectors derived from retroviruses, lentiviruses, adenovirus or adeno-associated virus (Girard et al. 2005; Watanabe et al. 2006; Sevin et al. 2007; Tannemaat et al. 2008; Harvey et al. 2009) have often been used as transduction or transformation vehicles for SCs, this is the first report of a beneficial effect conferred to SCs by a baculovirus (BmNPV)-derived vector. Baculovirus-derived vectors have several advantages over mammalian viral vectors such as lack of toxicity or pre-existing immunity, capacity to accommodate large inserts, and tropism towards many different cell types (Kost et al. 2005; Hu 2006; Kenoutis et al. 2006). "
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    ABSTRACT: 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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