A sensitive red/far-red photoswitch for controllable gene therapy in mouse models of metabolic diseases

Longliang Qiao, Lingxue Niu, Meiyan Wang, Zhihao Wang, Deqiang Kong, Guiling Yu and Haifeng Ye ()
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Longliang Qiao: East China Normal University
Lingxue Niu: East China Normal University
Meiyan Wang: East China Normal University
Zhihao Wang: East China Normal University
Deqiang Kong: East China Normal University
Guiling Yu: East China Normal University
Haifeng Ye: East China Normal University

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract Red light optogenetic systems are in high demand for the precise control of gene expression for gene- and cell-based therapies. Here, we report a red/far-red light-inducible photoswitch (REDLIP) system based on the chimeric photosensory protein FnBphP (Fn-REDLIP) or PnBphP (Pn-REDLIP) and their interaction partner LDB3, which enables efficient dynamic regulation of gene expression with a timescale of seconds without exogenous administration of a chromophore in mammals. We use the REDLIP system to establish the REDLIP-mediated CRISPR-dCas9 (REDLIPcas) system, enabling optogenetic activation of endogenous target genes in mammalian cells and mice. The REDLIP system is small enough to support packaging into adeno-associated viruses (AAVs), facilitating its therapeutic application. Demonstrating its capacity to treat metabolic diseases, we show that an AAV-delivered Fn-REDLIP system achieved optogenetic control of insulin expression to effectively lower blood glucose levels in type 1 diabetes model mice and control an anti-obesity therapeutic protein (thymic stromal lymphopoietin, TSLP) to reduce body weight in obesity model mice. REDLIP is a compact and sensitive optogenetic tool for reversible and non-invasive control that can facilitate basic biological and biomedical research.

Date: 2024
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DOI: 10.1038/s41467-024-54781-2

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