Year: 2018
Type: article
Abstract: Optogenetics, or the use of light-sensitive proteins to observe and control events in living cells, is considered one of the most groundbreaking innovations in neuroscience in recent years. By bestowing light sensitivity to retinal cells typically downstream of retinal damage/dysfunction, optogenetics has the potential to treat many diseases regardless of patient-specific mutations. This is a major advantage when (1) the mutation is unknown, (2) gene replacement has not yet proven feasible and (3) retinal neurons and supporting cells have undergone significant anatomical and functional remodelling. Despite several strengths with applications being explored in clinical trials, the use of optogenetics in ophthalmology prompts several considerations. Principally, most nonmodified microbial opsins used for ophthalmic applications require intense light for activation (between 1014 and 1017 photons/cm2/s). For example, blue light stimulation required by the most applied opsin (Channelrhodopsin-2) may variably exceed the safety threshold of artificial radiation for the human retina (International Commission on Non-Ionizing Radiation Protection 2013). Intense light stimulation is required for two reasons: (1) the relatively low expression level of opsins in transduced retina when compared to native visual pigment (due to toxic and immunologic concerns) as well as (2) the relatively weak signal generation of microbial ion channels or pumps (typically type 1 opsins) when compared to the G-protein coupled signal amplification of human rhodopsin (type 2 opsins). One approach to overcome the reliance on potentially damaging wavelengths of light is the creation of modified red-shifted opsins (Douar et al. 2016) allowing for activation at safer spectra. Another approach is the creation of photopharmacologic and optogenetic actuators with higher sensitivities. For example, engineered chemical photoswitches that bestow light sensitivity to endogenous transmembrane channels can be activated at 4 × 1013 photons/cm2/s. It is also possible engineer and/or apply more efficient opsins such as the modified human melanopsin (opto-mGluR6) conferring light sensitivity to retinal ganglion cells (RGCs) at 6 × 1012 photons/cm2/s (van Wyk et al. 2015) and human rod opsin conferring light sensitivity to retinal bipolar cells at 1012 photons/cm2/s.(Kapetanovic et al. 2017) An additional tool is to employ light-projecting goggles to capture the visual scene, amplify the light intensity of various features and project the image onto the retina at wavelengths optimized for opsin activation.(Goetz et al. 2013) Such goggles may also preserve the loss of meaningful visual mapping when nonphotoreceptor elements (bipolar cells or RGCs) generate the light-transduction signalling cascade. This is accomplished by projecting light in spatiotemporally altered patterns meaningful to various subpopulations of RGCs. Further limitations implicit in current optogenetic approaches are those pertaining to viral-based gene therapy. Briefly, these include the variable efficiency of viral transduction, non-specific opsin expression and off-target viral effects due to leaky promoters, the stability of expression with the potential for cellular toxicity due to gene product buildup and others. However, significant advancements have been made in viral-based gene therapy including the first FDA approved gene therapy (for Leber's congenital amaurosis) on 12/19/2017. A significant hurdle to the long-term efficacy of optogenetics yet to be addressed is retinal remodelling. This occurs in chronic dystrophic and degenerative diseases where the structure and function of remaining neuronal signalling pathways are disrupted. Even when prior considerations are addressed, targeting neurons that are mis-wired and/or functionally damaged limits meaningful visual gains. Retinal remodelling remains an issue of concern for all genetic, prosthetic and/or regenerative therapies for the retina and will need to be investigated further as a field. Optogenetics remains a remarkable neuroscientific tool with incredible promise for ophthalmology. This letter is not intended to discourage the use of optogenetics in a clinical setting, but rather to illuminate surmountable hurdles and to raise awareness for designing the next generation of ophthalmic optogenetic tools.
Source: Acta Ophthalmologica
DOI: 10.1111/aos.13779
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: bronze
Awards: G1876401501, G2916938824, G356571843
OpenAlex ID: W2806160068