Th41 - The Therapeutic Potential of Hematopoietic Stem Cell IL-1RA Gene Therapy for the Treatment of Hereditary IL-1-mediated Autoinflammatory Syndromes

Abstract Text: Systemic autoinflammatory diseases (SAIDs), including Cryopyrin-associated periodic syndrome (CAPS), are a group of devastating diseases characterized by recurrent episodes of systemic inflammation affecting various organs. There is no definitive cure for these patients. A desirable approach to treating these diseases may be the selective delivery of anti-inflammatory proteins to sites of inflammation. Thus, we used a lentiviral vector (LV) to target hematopoietic stem cell (HSC)-derived immune cells as vehicles for local delivery of the anti-inflammatory human IL-1 receptor antagonist (IL-1RA) protein in various mouse models of IL-1-mediated inflammatory diseases. Our gene-based approach may restore a balanced immune response and ameliorate disease. LV-derived IL-1RA production in mice and human HSCs did not alter their clonogenic and differentiation potential in vivo. We went on to demonstrate the efficacy of the IL-1RA gene therapy approach in various mouse models of IL-1-mediated inflammation. IL-1RA gene therapy suppressed the neutrophil recruitment induced by monosodium urate crystals, the etiological agent of gout. Moreover, mice receiving IL-1RA gene therapy were cured of CAPS-like symptoms, including weight loss, blood leukocytosis, and systemic and tissue inflammation. Lastly, IL-1RA gene therapy ameliorated the course of chronic progressive experimental autoimmune encephalomyelitis, reducing disease severity. Our data indicate that the HSC-based IL-1RA gene therapy approach can effectively correct tissue inflammation in different syndromes caused by IL-1 overproduction.