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<p>Optogenetic gene therapy is a promising mutation-independent treatment that aims to restore visual perception in patients blinded by retinal diseases that cause photoreceptor degeneration. Still, low sensitivity or slow kinetics of currently utilized optogenetic proteins limit the efficacy of such approaches. Here, we evaluated the therapeutic potential of three channelrhodopsin variants: ChRmine, from the algae <i>Rhodomonas lens</i>, ChRmine-T119A, a faster-closing ChRmine variant, and ChroME2s, a second-generation Chronos-based opsin.We expressed these opsins in retinal ganglion cells of <i>rd1</i> mice, a model of severe retinal degeneration. Single cell electrophysiology demonstrates opsin’s large sensitivity to a range of light intensities as well as opsin-expressing retinal ganglion cells generated action potentials in response to light stimulation. Behavioral tests showed ChRmine-T119A’s efficacy at 360&#xa0;lux compared to unmodified ChRmine and ChroME2s. ChRmine and ChroME2s did restore light perception at higher light intensities. Additionally, our dose–response study with ChRmine-T119A revealed that lower viral titers were more effective at restoring light sensitivity. Our study demonstrates that these ChRmine- and ChroME-based opsins can enhance vision in late-stage blinding diseases.</p>

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Optogenetic restoration of high-sensitivity vision using ChRmine- and ChroME-based channelrhodopsins

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月1日

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  • Victoria C. Fong,
  • Beatrice M. Le,
  • Antonia Stefanov,
  • Vivian Lee,
  • Seohyun Park,
  • Adithya Sivakumar,
  • Sabrina Spatny,
  • Meike Visel,
  • W. Rowland Taylor,
  • Stephen G. Brohawn,
  • John G. Flannery

摘要

Optogenetic gene therapy is a promising mutation-independent treatment that aims to restore visual perception in patients blinded by retinal diseases that cause photoreceptor degeneration. Still, low sensitivity or slow kinetics of currently utilized optogenetic proteins limit the efficacy of such approaches. Here, we evaluated the therapeutic potential of three channelrhodopsin variants: ChRmine, from the algae Rhodomonas lens, ChRmine-T119A, a faster-closing ChRmine variant, and ChroME2s, a second-generation Chronos-based opsin.We expressed these opsins in retinal ganglion cells of rd1 mice, a model of severe retinal degeneration. Single cell electrophysiology demonstrates opsin’s large sensitivity to a range of light intensities as well as opsin-expressing retinal ganglion cells generated action potentials in response to light stimulation. Behavioral tests showed ChRmine-T119A’s efficacy at 360 lux compared to unmodified ChRmine and ChroME2s. ChRmine and ChroME2s did restore light perception at higher light intensities. Additionally, our dose–response study with ChRmine-T119A revealed that lower viral titers were more effective at restoring light sensitivity. Our study demonstrates that these ChRmine- and ChroME-based opsins can enhance vision in late-stage blinding diseases.