Lipid Nanoparticle-mediated Fas Gene Immunotherapy Suppresses Autoimmune Lymphoproliferative Syndrome 3173

Abstract Description Autoimmune lymphoproliferative syndrome (ALPS) is a rare immunodeficient disease caused by FAS,mutation. ALPS patients are predisposed to both hematopoietic and solid malignancies. There is still no standard therapy or cure currently for ALPS. The recent breakthrough of COVID-19 mRNA vaccine opens a new avenue for nucleic acid-based therapy for a human disease. Based on this concept, we have created FAS codon usage-optimized cDNA-encoding nanoplasmid (NTC9385R-FAS). We have formulated NTC9385R-FAS with cationic lipid nanoparticle DOTAP-Cholesterol to generate a first-in-class FAS cDNA cationic lipid nanoparticle (termed FASCO01). The Fas-deficient (MRL/MpJ-Faslpr/J) exhibits systemic autoimmunity, massive lymphadenopathy associated with proliferation of aberrant T cells, arthritis, and immune complex glomerulonephrosis and is therefore an ALPS mouse model. We determined that Faslpr mice exhibit decreased lymphocyte apoptosis in vivo. To translate this FASCO01 to human ALPS therapy, we tested human lymphoma cell lines and determined that Fas expression is correlated with FasL-induced apoptosis in vitro. FasL induces caspase 3 activation and PARP cleavage. Furthermore, the Fas- lymphoblast K562 cells do not respond to FasL to activate caspase 3 and are resistant to FasL-induced apoptosis in vitro. The Fas- K562 xenograft is therefore a human ALPS model and is being tested in humanized NSG mice for hFASCO01 therapy efficacy in suppressing human ALPS in vivo. Funding Sources NIH: R01CA278852 Veterans Affairs: 101cx001364 Genprix Inc. GPEX00001 Topic Categories Basic Autoimmunity (BA)