The clinical potential of optogenetic interrogation of pathogenesis

• Published in: Clinical and translational medicine 2023-05, Vol.13 (5), p.e1243-n/a
• Main Authors: Gao, Tianyu Terry, Oh, Teak‐Jung, Mehta, Kritika, Huang, Yu‐En Andrew, Camp, Tyler, Fan, Huaxun, Han, Jeong Won, Barnes, Collin Michael, Zhang, Kai
• Format: Article
• Language: English
• Subjects: Accuracy; Biological products; channelrhodopsin; Clinical medicine; Clinical trials; CRISPR-Cas Systems; Disease; Empowerment; Genetic disorders; Genomes; Light; non‐opsin‐based; opsin‐based; optogenetics; Optogenetics - methods; Pathogenesis; Patients; photoactivatable proteins; Proteins; protein‐protein interaction; Retina; Review; Reviews; Signal transduction
• ISSN: 2001-1326; 2001-1326
• DOI: 10.1002/ctm2.1243

Background Opsin‐based optogenetics has emerged as a powerful biomedical tool using light to control protein conformation. Such capacity has been initially demonstrated to control ion flow across the cell membrane, enabling precise control of action potential in excitable cells such as neurons or muscle cells. Further advancement in optogenetics incorporates a greater variety of photoactivatable proteins and results in flexible control of biological processes, such as gene expression and signal transduction, with commonly employed light sources such as LEDs or lasers in optical microscopy. Blessed by the precise genetic targeting specificity and superior spatiotemporal resolution, optogenetics offers new biological insights into physiological and pathological mechanisms underlying health and diseases. Recently, its clinical potential has started to be capitalized, particularly for blindness treatment, due to the convenient light delivery into the eye. Aims and methods This work summarizes the progress of current clinical trials and provides a brief overview of basic structures and photophysics of commonly used photoactivable proteins. We highlight recent achievements such as optogenetic control of the chimeric antigen receptor, CRISPR‐Cas system, gene expression, and organelle dynamics. We discuss conceptual innovation and technical challenges faced by current optogenetic research. Conclusion In doing so, we provide a framework that showcases ever‐growing applications of optogenetics in biomedical research and may inform novel precise medicine strategies based on this enabling technology. Opsin‐based and opsin‐free optogenetics employs light to modulate membrane conductance and protein‐protein interaction. Clinical trials focus on treating blindness due to the easy delivery of light. Protein engineering improves the photophysics and biocompatibility of photoactivatable proteins. Opsin‐free optogenetics expands clinical applications such as the chimeric antigen receptor (CAR) and clustered regularly interspaced short palindromic repeats (CRISPR)‐based genomic engineering and transcriptional regulation.