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.
Keywords: Gene therapy, haematopoietic stem cell transplantation, haemophagocytic lymphohistiocytosis, lentiviral vector.
Current Gene Therapy
Title:Gene Therapy for Haemophagocytic Lymphohistiocytosis
Volume: 14 Issue: 6
Author(s): Claire Booth, Marlene Carmo and H. Bobby Gaspar
Affiliation:
Keywords: Gene therapy, haematopoietic stem cell transplantation, haemophagocytic lymphohistiocytosis, lentiviral vector.
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.
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Cite this article as:
Booth Claire, Carmo Marlene and Gaspar Bobby H., Gene Therapy for Haemophagocytic Lymphohistiocytosis, Current Gene Therapy 2014; 14 (6) . https://dx.doi.org/10.2174/1566523214666140918112113
DOI https://dx.doi.org/10.2174/1566523214666140918112113 |
Print ISSN 1566-5232 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5631 |
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