Abstract
Gene therapy presents an attractive alternative to allogeneic haematopoietic stem cell transplantation (HSCT) for treating patients suffering from primary immunodeficiency disorder (PID). The conceptual advantage of gene correcting a patient’s autologous HSCs lies in minimizing or completely avoiding immunological complications arising from allogeneic transplantation while conferring the same benefits of immune reconstitution upon long-term engraftment. Clinical trials targeting X-linked chronic granulomatous disorder (X-CGD) have shown promising results in this context. However, long-term clinical benefits in these patients have been limited by issues of poor engraftment of gene-transduced cells coupled with transgene silencing and vector induced clonal proliferation. Novel vectors incorporating safety features such as self-inactivating (SIN) mutations in the long terminal repeats (LTRs) along with synthetic promoters driving lineage-restricted sustainable expression of the gp91phox transgene are expected to resolve the current pitfalls and require rigorous preclinical testing. In this chapter, we have outlined a protocol in which X-CGD mouse model derived induced pluripotent stem cells (iPSCs) have been utilized to develop a platform for investigating the efficacy and safety profiles of novel vectors prior to clinical evaluation.
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Acknowledgements
The authors would like to thank the following funding agencies for their continued support: Wellcome Trust (UK), Great Ormond Street Hospital Children’s Charity (UK), and the European Union 7th Framework Program (PERSIST grant).
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Mukherjee, S., Thrasher, A.J. (2014). Gene Correction of Induced Pluripotent Stem Cells Derived from a Murine Model of X-Linked Chronic Granulomatous Disorder. In: Storici, F. (eds) Gene Correction. Methods in Molecular Biology, vol 1114. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-761-7_28
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DOI: https://doi.org/10.1007/978-1-62703-761-7_28
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