Lentiviral Gene Transfer Corrects Immune Abnormalities in XIAP Deficiency

Abstract

Background X-linked inhibitor of apoptosis protein (XIAP) deficiency is a severe immunodeficiency with clinical features including hemophagocytic lymphohistiocytosis (HLH) and inflammatory bowel disease (IBD) due to defective NOD2 responses. Management includes immunomodulatory therapies and hematopoietic stem cell transplant (HSCT). However, this cohort is particularly susceptible to the chemotherapeutic regimens and acutely affected by graft-vs-host disease (GvHD), driving poor long-term survival in transplanted patients. Autologous HSC gene therapy could offer an alternative treatment option and would abrogate the risks of alloreactivity. Methods Hematopoietic progenitor (Lin−ve) cells from XIAPy/− mice were transduced with a lentiviral vector encoding human XIAP cDNA before transplantation into irradiated XIAP y/− recipients. After 12 weeks animals were challenged with the dectin-1 ligand curdlan and recovery of innate immune function was evaluated though analysis of inflammatory cytokines, body weight, and splenomegaly. XIAP patient-derived CD14+ monocytes were transduced with the same vector and functional recovery was demonstrated using in vitro L18-MDP/NOD2 assays. Results In treated XIAPy/− mice, ~40% engraftment of gene-corrected Lin−ve cells led to significant recovery of weight loss, splenomegaly, and inflammatory cytokine responses to curdlan, comparable to wild-type mice. Serum IL-6, IL-10, MCP-1, and TNF were significantly reduced 2-h post-curdlan administration in non-corrected XIAPy/− mice compared to wild-type and gene-corrected animals. Appropriate reduction of inflammatory responses was observed in gene-corrected mice, whereas non-corrected mice developed an inflammatory profile 9 days post-curdlan challenge. In gene-corrected patient CD14+ monocytes, TNF responses were restored following NOD2 activation with L18-MDP. Conclusion Gene correction of HSCs recovers XIAP-dependent immune defects and could offer a treatment option for patients with XIAP deficiency.

Progress in the field of hematopoietic stem cell-based therapies for inborn errors of immunity

“…Several exciting preclinical GT results for IEI have been recently published. Topal et al demonstrated that LV GT corrects the immune abnormalities in XIAP-deficient mice [45], a particularly appealing treatment given the poor HCT outcomes seen in XIAP patients who develop GVHD [46,47]. Fox et al recently developed a gene editing strategy that inserts the CTLA-4 cDNA into the first intron of the CTLA-4 genomic locus in human T cells and corrects the lymphoproliferation in in vivo mouse models [48].…”