CORRECTION OF DEFICIENT ENZYME-ACTIVITY IN A LYSOSOMAL STORAGE DISEASE, ASPARTYLGLUCOSAMINURIA, BY ENZYME REPLACEMENT AND RETROVIRAL GENE-TRANSFER

The ability of lysosomal enzymes to be secreted and subsequently captu red by adjacent cells provides an excellent basis for investigating di fferent therapy strategies in lysosomal storage disorders. Aspartylglu cosaminuria (AGU) is caused by deficiency of aspartylglucosaminidase ( AGA) leading to interruption of the ordered breakdown of glycoproteins in lysosomes, As a consequence of the disturbed glycoprotein cataboli sm, patients with AGU exhibit severe cell dysfunction especially in th e central nervous system (CNS). The uniform phenotype observed in thes e patients will make effective evaluation of treatment trials feasible in future. Here we have used fibroblasts and lymphoblasts from AGU pa tients and murine neural cell lines as targets to evaluate in vitro th e feasibility of enzyme replacement and gene therapy in the treatment of this disorder. Complete correction of the enzyme deficiency was obt ained both with recombinant AGA enzyme purified from CHO-K1 cells and with retrovirus-mediated transfer of the AGA gene. Furthermore, we wer e able to demonstrate enzyme correction by cell-to-cell interaciton of transduced and nontransduced cells.