Application
Gene/cell therapy to treat hemophagocytic lymphohistiocytosis.
Key Benefits
- Gene therapy approach for treating patients with UNC13D mutated hemophagocytic lymphohistiocytosis.
- Preliminary in vitro and in vivo data show the ability of the gene therapy to increase UNC13D protein levels and decrease T cell activation.
- It is administered in combination with a stem cell transplant using genetically engineered hematopoietic stem cells.
Market Summary
Hemophagocytic lymphohistiocytosis (HLH) is a rare and potentially fatal disease afflicting about 1.2 million annually. It results in the over-activation of the immune system, leading to cytokine storm, organ failure, and death. In its inherited form, HLH is caused by mutations including PRF1, UNC13D, STX11, and/or STXBP2. Infections, autoimmune diseases, and cancer can trigger the acquired form of HLH. Treatment of HLH aims at suppressing hypercytokinemia and eliminating the activated and infected cells. In genetic HLH, hematopoietic stem cell transplantation (HSCT) is needed to correct the immune defect. Treatment modalities for acquired forms include immunosuppressives, cytostatic drugs, T-cell antibodies, and anti-cytokine agents. Still, these treatments are limited, and the lack of donor options limits timely transplants.
Technical Summary
Emory researchers are developing a gene therapy approach to treat genetic HLH that uses a codon-optimized expression vector to deliver the UNC13D to hematopoietic stem cells. The vector and transgene sequence have been designed to express up to 10-fold more UNC13D protein compared to the wild-type sequence. Thus far, the researchers have created a prototype of the gene therapy and demonstrated early proof of concept in vitro and in vivo using a UNC13D-deficient cell line. Treatment with the prototype led to significantly higher levels of UNC13D than the non-optimized construct. In addition, the overexpression led to a significant reduction in the number of activated T cells. The gene therapy could be used to modify cells before HSCT or administered directly to the patient’s T cells as a gene therapy.
Developmental Stage
Preliminary in vitro and in vivo data show the ability of the gene therapy to increase UNC13D protein levels and decrease T cell activation.