Long-term expression and transfer of arylsulfatase A into brain of arylsulfatase A-deficient mice transplanted with bone marrow expressing the arylsulfatase A cDNA from a retroviral vector

A deficiency of arylsulfatase A (ASA) results in the lysosomal lipid storag e disease metachromatic leukodystrophy. The disease mainly affects the cent ral nervous system causing a progressive demyelination. A therapeutic effec t will depend on the delivery of the deficient enzyme to the central nervou s system. We have transplanted ASA-deficient mice with bone marrow transduc ed with a retroviral vector expressing the human ASA cDNA. All transplanted animals initially showed high serum levels of human ASA. In 50% of the rec ipients high ASA serum levels were sustained for 12 months after transplant ation. in the remaining mice, serum levels decreased rapidly to low or unde tectable levels. ASA activity and immunoreactivity was detectable in all or gans of animals with continuous levels of ASA in serum. Most notably, subst antial amounts of ASA activity were transferred into the brain, reaching up to 33% of the normal tissue level. In contrast to peripheral organs, the a mount of enzyme delivered to the brain did not correlate with ASA serum lev els as an indicator of overexpression. This reveals that enzyme transfer to the brain is not due to endocytosis of serum ASA by endothelial cells, but rather to bone marrow-derived cells migrated into the brain.