Multiple Sulfatase Deficiency (MSD) is a rare, inherited lysosomal storage disorder (LSD) characterized by the functional deficiency of cellular sulfatases. MSD is caused by mutations in the gene SUMF1, which encodes formylglycine-generating enzyme (FGE), the enzyme that activates all sulfatases. Clinical features of MSD arise from the additive effects of each inactive sulfatase. Patients experience progressive neurologic symptoms, with a median age of death at 13 years. There are no approved disease-modifying therapies for MSD. However, ex vivo lentiviral gene therapy with hematopoietic stem cell transplant (HSCT) is an EMA-approved therapy for metachromatic leukodystrophy (MLD) and is being developed for other related single-sulfatase disorders (i.e. MPSIIA and MPSII). We aim to evaluate the efficacy of autologous HSCT with ex vivo lentiviral correction of SUMF1 in MSD. In this approach, stem cells isolated from patient bone marrow are transduced with a lentiviral vector expressing SUMF1 prior to transplant. Ideally, after transplant, corrected cells will secrete high levels of activated sulfatases, correcting neighbouring enzyme-deficient cells. In preliminary work we have tested the efficacy of a construct expressing SUMF1 by transducing two fibroblast cell lines derived from MSD patients. We found a dose-dependent increase in SUMF1 expression, arylsulfatase A (ARSA) and B (ARSB) activity in both patient lines.
We hypothesize that outcomes may be further improved by introducing both SUMF1 and key target sulfatases that are decreased in MSD patients. In preliminary studies, we found that introduction of both SUMF1 and ARSA further increases ARSA activity in MSD patient cells as compared to the introduction of SUMF1 alone. Here, we will evaluate if HSCT with ex vivo lentiviral correction of SUMF1 (or co-expression with key target sulfatases) will increase sulfatase activities, reduce storage material accumulation, and correct disease phenotypes in cell and mouse models of MSD
