Introduction:
Optogenetics uses light to either regulate or observe brain activity. It works by genetically introducing light-sensitive proteins to the desired cells. Optogenetics came up as a result of the identification of optogenetic actuators such as archaerhodopsin (Arch), channelrhodopsin (ChR), and halorhodopsin, which may alter excitable cell membrane potential and neuronal activity.
Sonogenetic treatment is another approach that aims to regulate neural activity by using ultrasonic waves in response to producing an ultrasonic-sensitive protein in neurons through genetic expression. Sonogenetic neuromodulation is a relatively new concept in neuroscience, whereas optogenetics is well-established. However, both treatments help in various forms of blindness by providing vision restoration.
How Does Optogenetics Help to Treat Retinal Degenerative Diseases?
Optogenetics has the most potential to treat retinal degenerative disorders. Retinitis pigmentosa (RP) (a group of rare eye diseases affecting the retina) is one of the leading causes of blindness in developed countries, accounting for around 1 in 4000 cases globally. It is a hereditary retinal degenerative disease. Retinal degenerative disorders with varying genetic makeup are collectively referred to as RP. Patients with RP share a common pathogenesis of photoreceptor cell death.
After photoreceptors in RP patients are lost, the inner retinal layer, which includes bipolar cells and RGCs, is known to be retained for a specific amount of time. Optogenetic therapy may thereby target the inner retinal layer. To treat retinal degenerative illnesses, optogenetic therapy involves expressing light-activated proteins to transform residual non-photoreceptor retinal cells into artificial photoreceptors.
How Is Optogenetic Vision Restoration Done at the Retinal Level?
Currently, the most effective restoration of visual acuity for blind individuals is provided by the PRIMA retinal prosthesis (Pixium Vision, Paris, France). It has been tested on individuals with dry age-related macular degeneration; this retinal prosthesis allowed patients to combine their natural peripheral vision and central infrared artificial vision, resulting in a prosthetic visual acuity between 20/460 and 20/565.
Achieving a single-cell resolution will be extremely challenging, even with future technological advancements. Optogenetic therapy may enable cellular resolution by making the remaining retinal neurons light-sensitive. It was initially demonstrated that, even in total photoreceptor loss in rd1 mice, retinal ganglion cells could still express channelrhodopsin2 (ChR2) and react to light. Research findings also validated the possibility of restoring light sensitivity following total photoreceptor degeneration using ChR2 expression in retinal ganglion cells.
Optogenetics cannot independently replicate the vast anatomical and functional diversity of retinal ganglion cells in each cell type, leading to a variety of light responses. Every retinal ganglion cell type changes into a different cell type without affecting the original one. Several ways were presented to increase variability by targeting retinal information processing sequence cells.
The most effective technique would be to reactivate "dormant" cone photoreceptors after reducing natural photosensitivity. These situations allow for the restoration of complex information processing, but only a small percentage of patients with retinal dystrophies have such latent non-photosensitive photoreceptors.
Mammalian opsin has been expressed ectopically in several laboratories to restore eyesight because microbial opsins are light-sensitive and may trigger an adverse immune response. The first opsin targeted in retinal ganglion cells was melanopsin, already found in a limited population as an innately photosensitive retinal ganglion cell with non-visual functions.
Because of this opsin, all transfected retinal ganglion cells were intrinsically light-sensitive. However, these melanopsin-expressing cells had light-sensitive responses that lasted for minutes and were therefore, incompatible with normal vision.
Finally, optogenetic gene therapy was paired with cell therapy since photoreceptors produced by induced pluripotent stem cells cannot create effective photosensitive outer segments. This method allows the transplant of active photoreceptors in advanced stages of retinal degeneration. The visual responses and behavior of blind animals were restored by transplantation-modified photoreceptors expressing inhibitory microbial opsins.
How Is Optogenetic Vision Restoration Done at the Cortical Level?
In the 1960s, Brindley and Lewin developed cortical visual prostheses to treat disorders leading to blindness after losing the optic nerve. These devices successfully elicited phosphenes in the visual field, supporting Braille reading. But for many patients, the sight they had regained gradually faded. Thus, cortical visual prosthesis studies have validated the search for non-contact, remote cortical neuronal activation.
Optogenetic therapy emerged as a clear, non-contact option for distant stimulation of cortical neurons through the brain surface. Cortical neurons were discovered to be activated even in the cortex after surface illumination of the brain when a microbial opsin was expressed in the visual cortex.
Functional magnetic resonance imaging (fMRI) revealed that this cortical activation in non-human primates stimulated activity in other visual areas and caused visual saccades toward the relevant point in the visual field.
Optogenetic stimulation only produced more subtle changes, including increased sensitivity to the stimulus orientation, if it was performed on a column with orientation selectivity similar to the stimulus. Additionally, optogenetic stimulation of single ocular dominance columns produced preferential activation of adjacent same-eye columns. Future therapeutic applications should consider the fact that light dispersion and absorption in brain tissue make deep brain optogenetic stimulation challenging.
Conclusion:
Genomic approaches based on gene therapy that create ectopically photosensitive and mechanosensitive ion channels might produce high-resolution brain-machine interfaces. Clinical trials with optogenetics have shown that individuals with retinitis pigmentosa may be partially restored. Additional examinations are required to determine whether patients can achieve the theoretical visual acuity (20/72) estimated in ex vivo research on the retina of non-human primates.
Hence, the outcome of ongoing clinical trials will determine if optogenetics can offer an excellent replacement for retinal prosthetics regarding vision restoration. Similarly, sonogenetic therapy replaces cortical prosthetics with deep, non-contact cortical stimulation through the dura mater. Before initiating clinical trials, additional research is required to assess the safety and effectiveness of this approach. Despite these drawbacks, sonogenetics offers immense potential for a new generation of brain-machine interfaces for neurological applications and cortical vision restoration.
