Long-term expression, systemic delivery, and macrophage uptake of recombinant human glucocerebrosidase in mice transplanted with genetically modified primary myoblasts.

A critical requirement for treatment of Gaucher disease via systemic delivery of recombinant GC is that secreted enzyme be in a form available for specific takeup by macrophages in vivo. In this article we investigated if transplanted primary myoblasts can sustain expression of human GC in vivo and if the secreted transgene product is taken up by macrophages. Transduced primary murine myoblasts were implanted into syngeneic C3H/HeJ mice. The results demonstrated that transplanted mice sustained long-term expression of transferred human GC gene in vivo. Furthermore, human GC is secreted into the circulation of mice transplanted with syngeneic primary myoblasts retrovirally transduced with human GC cDNA. The transplanted primary myoblasts differentiate and fuse with adjacent mature myofibers, and express the transgene product for up to 300 days. Human GC in the circulation reaches levels of 20-280 units/ml of plasma. Immunohistochemical studies of the target organs revealed that the secreted human GC is taken up by macrophages in liver and bone marrow. Immunochemical identification of reisolated myoblasts from transplanted mice showed that MFG-GC-transduced cells also survived as muscle stem cells in the implanted muscle. These results present in encouraging prospect for the treatment of Gaucher disease.