Therapeutic Evaluation of Subcutaneously Delivered, Alginate-Encapsulated, Genetically Engineered Mesenchymal Stem Cells for Fabry disease

Abstract

Fabry disease is an X-linked lysosomal storage disorder caused by α-galactosidase A (α-Gal A) deficiency, leading to globotriaosylceramide accumulation. Current enzyme replacement therapy (ERT) requires biweekly intravenous infusions, presenting significant limitations in patient compliance and quality of life. In this study, we developed a long-term delivery system using genetically engineered mesenchymal stem cells (eMSCs) encapsulated in alginate microgels. Human α-galactosidase A-expressing eMSCs maintained high viability and stable enzyme secretion after encapsulation, and subcutaneous injection of these αGal-eMSC-Alg constructs demonstrated structural stability for up to 12 weeks in nude mice. Therapeutic efficacy in GLA knockout Fabry mice showed age-dependent outcomes, with the aged group exhibiting better trends of eMSC survival and reduced kidney Gb3 accumulation compared to the young group. This αGal-eMSC-alginate system offers single-injection, long-term therapeutic delivery advantages over conventional enzyme replacement therapy, representing a promising platform for lysosomal storage disorders with potential for optimization through further investigation of enhanced immune evasion strategies.