The current proposal is designed to test whether a retroviral vector developed from the Foamy virus (FV) can be used as a therapeutic vehicle to correct a human genetic disorder that affects the cells of the haematopoietic system. FV vectors are developed from the non-pathogenic foamy retrovirus and have been shown to transduce haematopoietic stem cells (HSC) of both murine and human origin. FV-based vectors show promise for therapeutic gene delivery into HSC and offer an alternative technology to the existing retro and lenti vector systems. As a next step in FV vector development, we plan the genetic correction of Chronic Granulomatous Disease (CGD), a disorder that results from the absence of NADPH-oxidase in the phagocytes of the peripheral blood and impaired killing of ingested microorganisms. Affected patients present with severe bacterial and fungal infections, which appear early on in life and may be fatal.
The commonest form of CGD is X-linked and results from the absence of the gp91phox subunit of NA DPH. The relative knockout mouse model (X-CGD) closely mimics the human disease phenotype and will be used in this study. Preliminary studies with the X-CGD mouse model will aim at optimising transduction conditions for HSC gene transfer using reporter genes driven by constitutive and tissue-specific promoters. Following these studies, we will use the optimised conditions to transfer the therapeutic gene into the HSC of the X-CGD animals and will assay disease correction by standard assays. Finally, we will target CD34+ cells from individuals with CGD and evidence for disease correction will be obtained from both in vitro assays and after BMT into NOD/SCID mice. The experiments as described will provide us with the necessary data in a pre-clinical model of a human disease for which bone marrow transplantation is the only treatment option. The information obtained will be used for the rational design of a human gene therapy trial for affected patients.
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