Lentiviral gene therapy for familial hemophagocytic lymphohistiocytosis type 3, caused by UNC13D genetic defects.

Familial hemophagocytic lymphohistiocytosis type III (FHL3) is a rare disease caused by mutations to the UNC13D gene and the subsequent absence or decreased activity of the Munc13-4 protein. Munc13-4 is essential for the exocytosis of perforin and granzyme containing granules from cytotoxic cells. Without it, these cells are able to recognize an immunological insult but are unable to execute their cytotoxic functions. The result is a hyper-inflammatory state that, if left untreated, is fatal. Currently, the only curative treatment is hematopoietic stem cell transplantation (HSCT), but eligibility and response to this treatment are largely dependent on the ability to control inflammation prior to HSCT. In this study, we describe an optimized lentiviral vector that can restore Munc13-4 expression and degranulation capacity in both transduced FHL3 patient T cells as well as transduced hematopoietic stem cells from the FHL3 (Jinx) disease model.