Lipid Nanoparticle Fas Gene Therapy Suppresses Autoimmune Lymphoproliferative Syndrome in Mice

Autoimmune lymphoproliferative syndrome (ALPS) is a genetic disease of deregulated leukocyte homeostasis caused by FAS gene mutation or loss of Fas function. Despite three decades having passed since its discovery, except for bone marrow stem transplantation, there is currently no effective treatment for ALPS. The recent breakthrough of COVID-19 mRNA vaccine demonstrated the effectiveness of nucleic acid-based therapy for a human disease. We determined that Fas mediates caspase activation-dependent apoptosis of human hematopoietic cells in vitro. In the ALPS mice, loss of Fas function leads to decreased hematopoietic cell spontaneous apoptosis and mass accumulation of lymphocytes. To restore Fas expression and function, we generated lipid nanoparticle-encapsulated Fas-encoding plasmid (LNP-mFas). LNP-mFas therapy decreased the accumulation of CD4^-CD8^- lymphocytes and increased CD4⁺ and CD8⁺ mature T cells in mice, resulting in suppression of ALPS in mice. We therefore determine that LNP-mFas is potentially an effective therapy for ALPS.