Correction of enzyme deficiency in metachromatic leukodystrophy fibroblasts by retroviral‐mediated transfer of the human arylsulphtase A gene

Metachromatic leukodystrophy (MLD) (McKusick 25000, 25010, 25020) is a recessively inherited metabolic disease and one of the most prevalent dysmyelinating diseases in the paediatric age group. It is characterized by accumulation of cerebroside sulphate because of a deficient activity of a lysosomal enzyme, known as arylsulphatase A (ASA; EC 3.1.6.8) (Kolodny 1989). Cerebroside sulphate is the primary substrate of ASA and also one of the lipid components in the myelin sheath. Its storage causes the dysmyelinating process in MLD. So far, the only approach of clinical benefit for MLD has been allogenic bone marrow transplantation (BMT) (Krivit et al 1990). Although MLD patients have responded to BMT, inherent problems limit its application: the limited number of donors and the risk of graft-versus-host disease. These limitations have stimulated the consideration of MLD as a good candidate for therapy based on gene transfer to haematopoietic cells. In this paper we describe the successful transduction and expression of the ASA gene in human MLD fibroblasts using a newly developed retroviral vector. Our earlier study with this vector demonstrated efficient transduction and sustained expression of the human glucocerebrosidase gene in murine haemoatopoietic stem cells and their progeny (Ohashi et al 1992). We have constructed a similar retroviral vector for the transfer of the ASA gene, MFG-ASA, and tested its ability to restore the enzyme deficiency in human fibroblasts as a first step in evaluating the potential of gene therapy for MLD.