Grants Awarded

Principal Investigator
Peter Aichele, PhD
University Medical Center Freiburg, University of Freiburg – Freiburg, Germany

Date of Award
December 2013

Amount of Award
$49,920

Layperson Summary
XLP1 (X-linked lymphoproliferative disease) is an immunodeficiency based on genetic defects in the SAP molecule. XLP patients suffer from a variety of clinical manifestations with the most prominent being i.) chronic activation of T cells and macrophages, ii.) impaired antibody production and iii.) high-risk to develop distinct cancer. So far, the only possibility to cure XLP patients is to replace their immune system by bone marrow transplantation (transfer of stem cells of the blood system). However, such a therapeutic approach carries certain risks as the transfer of stem cells from an unrelated donor may lead to rejection of the new immune system by the recipient. Such a risk would not exist, if a gene-corrected version of the patients own stem cells is transferred. However, such a gene therapy approach has to be controlled very tightly and has to be proven in a suitable animal model in advance. Mice deficient for SAP are such a model, as they develop a XLP-like disease after infection with a defined virus.

Our aim is to test whether virus-triggered XLP disease in SAP-deficient mice is cured after transfer of their own gene-corrected stem cells or by transfer of their own gene-corrected mature T cells. If our therapeutic approach is successful in the mouse model, this will be an important step to establish gene therapy for XLP patients, with the advantage of less side effects compared to the current therapeutic protocols. Thus, our proposal focuses on the therapy of a histiocytic disorder with the aim to improve therapy management for XLP patients.

Twelve Month Report
X-linked lymphoproliferative disease (XLP1) is an immunodeficiency based on defects in a gene called SAP (SLAM associated protein). The clinical features of the disease (XLP1 syndrome) are quite variable but typically include i) a failure to generate antibodies, ii) a problem to control an infection with Epstein Barr Virus and iii) tumor development. So far, the only curative option in XLP patients is the replacement of the defective immune system by hematopoietic stem cell transplantation (HSCT), which is often limited by donor availability. Therefore, gene therapy may be an attractive alternative, where the patients own immune system is corrected. In this project, we aimed to test the in vivo efficacy of such a therapeutic approach in an animal model. For this, hematopoietic stem cells from SAP-deficient mice were gene corrected and transferred into irradiated SAP-deficient mice to generate a new immune system without the defect in the SAP gene. Then gene-corrected SAP-deficient mice were infected with a virus (Lymphocytic Choriomeningitis Virus, LCMV) to trigger disease and analyzed whether gene-corrected cells of the immune system can prevent development of the XLP-like syndrome. We could demonstrate that SAP-deficient mice developed a less severe XLP-like disease after gene therapy and were able to generate B cells that produce antibodies. This attenuated disease progression and the immune phenotype of gene-corrected SAP-deficient mice resembled that of WT mice, which did not develop the disease. Thus we showed that a gene therapy approach successfully cured XLP-deficiency in an animal model.