Special aspects of stem cell therapy in patients with MLD

Metachromatic leukodystrophy (MLD) is caused by mutations in the arylsulfatase A (ASA) gene and leads to demyelination in the CNS. In MLD, transplantation of hematopoietic stem cells is thought to establish a continuous endogenous source of ASA, which can be taken up by somatic cells of the recipient to correct their own lysosomal metabolism. We analysed 8 patients with MLD after transplantation regarding (i) toxicity of a reduced intensity condition regimen; (ii) the potential benefit of co-transplantation of MSC; and (iii) GvHD prophylaxis. i) All patients were transplanted successfully and reached complete donor chimerism with low toxicity. Three patients developed transiently acute GvHD of the skin II°. Patients who were symptomatic showed slight progression and then stabilized early after transplant. ii) We sought to improve the HSCT by co-transplantation of multipotent mesenchymal stromal cells (MSCs). We showed that MSCs release significant amounts of ASA in vitro, may cross the blood-brain barrier in an inflammatory environment and home to the CNS. iii) Post-transplant GvHD prophylaxis with cyclosporine A may be problematic for MLD patients, because CsA is not only neurotoxic by itself, but also compromises ASA activity.