Gene therapy for haemophagocytic lymphohistiocytosis.

Abstract

Haemophagocytic lymphohistiocytosis (HLH) describes a severe and often fatal immunodysregulatory disorder caused primarily by the uncontrolled activation and proliferation of T cells and macrophages. A number of genetic defects mainly involving defective granule exocytosis and effector cell cytotoxicity have been identified and well characterised at the molecular and cellular level. These conditions have limited therapeutic options and given the predominant restriction of the causative gene to the haematopoietic system, they have become attractive targets for haematopoietic cell gene therapy. Pre clinical studies in murine models of HLH due to perforin deficiency have shown correction of the disease phenotype as a result of autologous haematopoietic stem cell (HSC) gene transfer using lentiviral vectors. In a murine model of X-linked lymphoproliferative disease (XLP1), HSC gene transfer is able to correct the immunological manifestations of the disease. These encouraging murine studies have led to further work to develop clinically applicable strategies. An alternative approach is to correct defective T cells as this approach is safer than HSC gene therapy and may allow early control of the HLH through the engraftment of functional gene modified effector T cells. Both strategies are now in development and a gene therapy option for certain genetic forms of HLH may soon enter clinical trials.