HLH (of all genetic etiologies) has a 20-50% mortality rate despite aggressive immunosuppressive therapy and bone marrow transplantation (BMT); therefore, we are eager to identify additional therapeutic interventions that improve cytotoxic function in patients with HLH. Gene transfer (also known as gene therapy) offers the capacity to restore cytotoxicity and therefore eliminate antigen-presenting cells (APCs) by restoring the abnormal proteins of the cytotoxic pathway. Currently, none of our therapeutic maneuvers target this first step in the inflammatory cascade. Instead, current treatments focus on suppressing immune cells after persistent activation by APCs. Our long-term goal is to develop a gene therapy program for patients with all forms of genetically defined HLH. In the current project, we will test the feasibility of gene transfer to correct perforin deficiency in patient-derived cytotoxic lymphocytes.
Dr. Punam Malik, Dr. Filipovich, and Dr. Michael Jordan.
Dr. Malik is the Program Leader for the Molecular and Gene Therapy Program at Cincinnati Children’s. She is currently coordinating a clinical trial for gene therapy in beta thalassemia and sickle cell anemia. She directs the viral vector production lab that is the exclusive producer of clinical grade self-inactivating (SIN) lentivirus driven by a cellular promoter for the international trial for X-linked severe combined immunodeficiency (SCID), already underway.
Dr. Filipovich is the clinical director of the Immunodeficiency and Histiocytosis Program at Cincinnati Children’s and also a co-investigator on the X-linked SCID gene therapy trial. She and Dr. Jordan will assist in identifying and consenting patients with FHL2 so that we may obtain blood and bone marrow samples for research.
In addition, Dr. Jordan is testing the utility of the lentiviral vectors in a pre-clinical murine model of FHL2.