BG147 promises to transform ex vivo and in vivo gene therapies by transiently inhibiting intrinsic immune barriers mediated by IFITM3 to enhance a wide range of protocols.
Abstract
Intrinsic innate immune barriers have evolved to suppress viral infection and can reduce effective gene delivery in gene therapy. We have developed BG147, a novel cyclosporine A (CsA) analogue optimised via structure-guided design to specifically inhibit interferon-induced transmembrane proteins (IFITM1-3) but not inhibit CsA target, and HIV cofactor, cyclophilin A. BG147 enhances VSV-G pseudotyped lentiviral vector transduction ex vivo in hematopoietic stem and progenitor cells (HSPCs) and in in vivo ocular gene therapy of photoreceptor cells in mice. Upon BG147 treatment, IFITM3 protein is mislocalised and degraded through lysosomal acidification-dependent pathways but returns 96 h after BG147 washout. Critically, HSPC transduced in the presence of BG147 showed successful engraftment in NGS mice. BG147 promises to transform ex vivo and in vivo gene therapies by transiently inhibiting intrinsic immune barriers mediated by IFITM3 to enhance a wide range of protocols.
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