What is the role of gene therapy in the treatment of X-linked lymphoproliferative (XLP) syndrome?

Updated: Jan 27, 2019
  • Author: Karen Seiter, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Gene therapy offers the advantages of reduced toxicity from conditioning as, in general, less chemotherapy is required and the use of autologous cells removes the risk of graft versus host disease which causes significant morbidity and mortality post HSCT. [19]

Rivat et al reported a preliminary study in mice in which the immune function defects of XLP syndrome were corrected by lentiviral vector-mediated gene transfer of SH2D1A into autologous hematopoietic stem cells. The transfer of gene-corrected cells led to the restoration of natural killer (NK) and CD8 T cell cytotoxicity, NKT development, as well as GC formation and function upon immunological challenge. [20] However, SAP is a tightly regulated signaling protein that is predominately expressed in T cells, and the use of a ubiquitous human promoter that can drive expression in all hematopoietic cells may not be optimal.

An alternative therapeutic strategy to more directly address the T cell–dependent clinical manifestations of XLP1 is gene correction of the patient's own T cells. Murine studies utilizing gene-modified T cell transfers into mice demonstrated the correction of T follicular helper cell function, the restoration of germinal centers, and the improvement in baseline immunoglobulin levels. In addition, the correction of CD8+ T cell function was shown using an in vivo tumor model. These data support  gene therapy as a potentially useful therapeutic option. [6]

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