Lentiviral Gene Transfer Corrects Immune Abnormalities in XIAP Deficiency

Area of Science:

• Immunology
• Gene Therapy
• Hematology

Background:

• X-linked inhibitor of apoptosis protein (XIAP) deficiency is a severe immunodeficiency characterized by hemophagocytic lymphohistiocytosis (HLH) and inflammatory bowel disease (IBD).
• Current management involves immunomodulatory therapies and hematopoietic stem cell transplant (HSCT), but patients face high risks from chemotherapy and graft-vs-host disease (GvHD), leading to poor long-term survival.
• Autologous HSC gene therapy presents a potential alternative, mitigating risks associated with alloreactivity.

Purpose of the Study:

• To evaluate the efficacy of autologous hematopoietic stem cell (HSC) gene therapy in correcting XIAP deficiency.
• To assess the recovery of innate immune function in a mouse model and patient-derived cells following gene correction.

Main Methods:

• Hematopoietic progenitor cells from XIAP-deficient mice were transduced with a lentiviral vector encoding human XIAP cDNA and transplanted.
• Gene-corrected XIAP patient-derived monocytes were assessed using in vitro NOD2 activation assays.
• Mice were challenged with curdlan to evaluate innate immune recovery by analyzing inflammatory cytokines, body weight, and splenomegaly.

Main Results:

• Gene-corrected HSCs in XIAP-deficient mice led to approximately 40% engraftment, significantly restoring weight, reducing splenomegaly, and normalizing inflammatory cytokine responses to curdlan.
• Serum levels of IL-6, IL-10, MCP-1, and TNF were significantly reduced in gene-corrected mice post-curdlan challenge compared to non-corrected mice.
• Gene-corrected patient monocytes demonstrated restored TNF responses upon NOD2 activation.

Conclusions:

• Gene correction of HSCs effectively recovers XIAP-dependent immune defects.
• This gene therapy approach holds promise as a potential treatment for patients with XIAP deficiency, offering an alternative to traditional HSCT.