Efficient and sustained optogenetic control of sensory and cardiac systems.

Summary

The authors engineer ChReef, a red-shifted opsin with minimal desensitization and fast closure that achieves stable, low-light optogenetic pacing and depolarization block in cardiomyocyte clusters. AAV delivery to retinal ganglion cells restores vision in blind mice under weak illumination, and nanojoule-threshold auditory pathway activation is demonstrated in rodents and non-human primates, supporting LED-based optical cochlear implants.

Key Findings

• Engineered opsin ChReef showed minimal photocurrent desensitization, unitary conductance ~80 fS, and ~30 ms closing kinetics enabling reliable low‑light control.
• Red‑light optical pacing and depolarization block were achieved in ChReef‑expressing cardiomyocyte clusters.
• AAV‑mediated ChReef expression in retinal ganglion cells restored visual function in blind mice under very low illumination (e.g., tablet screen).
• Auditory pathway stimulation at nanojoule thresholds was demonstrated in rodents and non‑human primates, supporting LED‑based optical cochlear implants.

Clinical Implications

While preclinical, ChReef suggests a future route to light-based cardiac pacing/defibrillation and sensory neuroprosthetics with potentially reduced energy, improved spatial selectivity, and minimized tissue heating compared with electrical approaches.

Limitations

• Preclinical proof‑of‑concept without long‑term safety or arrhythmia efficacy testing in large‑animal hearts
• Clinical translation depends on safe gene delivery, immunogenicity control, and optical energy delivery strategies

Future Directions

Evaluate long‑term cardiac safety and efficacy in large‑animal arrhythmia models, optimize delivery (AAV serotypes, promoters) and light hardware, and compare against electrical pacing in energy, selectivity, and tissue effects.