We have investigated the ability of a receptor-mediated gene transfer strategy (cross-correction) to restore ganglioside metabolism in TS fibroblasts in vitro. Tay-Sachs (TS) disease is a GM2 gangliosidosis due to the deficiency of the lysosomal enzyme beta-hexosaminidase A (Hex A, E.C. 3.2.1.52. The hypothesis is that co-cultures of transduced cells over-expressing and secreting large amounts of the enzyme with defective TS cells, would lead to a measurable activity in the latter via a secretion-recapture mechanism. We transduced NIH3T3 murine fibroblasts with the LaHexTN retroviral vector carrying the cDNA encoding for the human Hex alpha-subunit. The Hex activity in the medium from transduced cells was about 10 fold higher (up to 75 mU) than observed in untransduced cells. TS cells were cultured for 72 hrs in the presence of the cell medium derived from the transduced NIH3T3 cells and were analyzed for the presence and for the catalytic activity of the enzyme. Although TS cells were able to efficiently uptake large amount of the soluble enzyme, it failed to reach the lysosomes in a sufficient quantity to hydrolyze the GM2 ganglioside to GM3 ganglioside. Thus, our results showed that delivery of the therapeutic Hex A was not sufficient to correct the phenotype of TS cells.