Keywords

Optogenetics is a technique that allows for the optical control of neural activity (Boyden et al. 2005; Deisseroth et al. 2006; Häusser 2014) by using light-sensitive ion channels or pumps derived from algae or bacteria (e.g., channelrhodopsin or halorhodopsin) (Nagel et al. 2003; Oesterhelt and Stoeckenius 1971; Sugiyama and Mukohata 1984), as well as other optogenetic tools, such as vertebrate opsins (Herlitze and Landmesser 2007). In a degenerated blind retina, the specific expression of optogenetic tools enables to convert specific retinal cells types into “artificial photoreceptors ” (Sahel and Roska 2013).

Depending on the degenerative state of the retina, different optogenetic strategies can be used (Fig. 9.1). Targeting of retinal photoreceptors could be an option for RP patients with remaining cone cell bodies lacking their light-sensitive outer segments. Anatomical studies, using postmortem retinal tissue (Lin et al. 2009) or in vivo imaging (optical coherence tomography) from RP patients (Jacobson et al. 2013), have shown that some patients with late-stage RP had residual cone cell bodies. These observations suggest that there are candidates who could be eligible for photoreceptor-based strategies . In the mouse model, the reactivation of nonfunctional but surviving “dormant” cones, using the light-sensitive chloride pump halorhodopsin, has been shown by Botond Roska’s group (Busskamp et al. 2010). Halorhodopsin was able to substitute for the impaired phototransduction cascade in treated blind mice. These reactivated cones could drive retinal circuit functions, including lateral inhibition and directional selectivity, and they mediated cortical processing as well as visually guided behavior. Moreover, human retinal explants were used to reactivate light-insensitive photoreceptors with halorhodopsin, demonstrating the functionality of the microbial opsin in the human retina.

Fig. 9.1
figure 1

Schematic diagram of a healthy retina compared to retinae with progressive degeneration and circuit remodeling. The choice of the therapeutic strategy is determined by the availability of persisting cell types, ranging from targeting “dormant” cones (1), bipolar cells (2), to retinal ganglion cells (3). Horizontal cells and amacrine cells are shown in dark purple and yellow, respectively. INL inner nuclear layer

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However, it is unknown how long synaptic connection from photoreceptors to bipolar cells will remain under degenerative conditions. Therefore, cell type-specific targeting of optogenetic tools to retinal bipolar cells would be another attractive option. In a pioneering study, Lagali et al. used electroporation to express channelrhodopsin (ChR2) under control of the ON bipolar cell promoter in ON bipolar cells of blind mice (rd1), leading to the recovery of visually evoked potentials in the cortex and visually guided behavior (Lagali et al. 2008). Electroporation, however, had to be replaced by viral gene delivery suitable for potential clinical applications. Meanwhile, AAV-based vectors with improved retinal diffusion properties have been developed (Dalkara et al. 2013), and it has been shown that these engineered AAVs can efficiently deliver ChR2 variants to ON bipolar cells (Cronin et al. 2014; Macé et al. 2015) of blind mice. Importantly, ChR2 targeted to ON bipolar cells restored both ON and OFF component of the visual responses, which is mediated by inner retinal processing. The restoration of the ON/OFF pathway was also observed in the retina and in the visual cortex. In addition, light-induced behavior was observed in these treated blind mice (Cehajic-Kapetanovic et al. 2015; Gaub et al. 2014, 2015; Macé et al. 2015; van Wyk et al. 2015), but targeting of bipolar cells has not yet been accomplished in non-human primates.

Finally, optogenetic targeting of ganglion cells could be a therapeutic strategy for patients with late-stage degeneration and advanced remodeling of inner retinal circuits (Jacobson et al. 2013; Jones et al. 2016). Bi and Pan were the first to show that light sensitivity can be restored through expression of ChR2 in retinal ganglion cells after complete photoreceptor degeneration (Bi et al. 2006), which was followed by other studies (Caporale et al. 2011; Greenberg et al. 2011; Ivanova and Pan 2009; Lin et al. 2008; Sengupta et al. 2016; Tomita et al. 2010; Tomita et al. 2007; Wu et al. 2013; Zhang et al. 2009). A disadvantage of this approach is that neural circuits upstream of ganglion cells cannot be utilized. On the other hand, clinical studies using direct electrical stimulation of ganglion cells with epiretinal implants have shown that patients are able to perform visual tasks, such as object localization or motion discrimination (Humayun et al. 2012; Shepherd et al. 2013). This indicates that the plasticity of higher brain regions can compensate for some loss of retinal image processing and that the human cortex has the capability to adapt to a visual code that is different from the natural activity pattern conveyed by a healthy retina.

In summary, optogenetics enables to confer light sensitivity to distinct retinal cell types, thus offering new therapeutic approaches to restore vision in a wide range of retinal degenerative diseases. In a future perspective, combined approaches of optogenetics with neuroprotection could be a therapeutic option, not only to restore the function of remaining cells but also to rescue retinal structures from progressive degeneration (Sahel and Roska 2013). Although the therapeutic benefits of optogenetic approaches remain to be determined, first steps toward clinical application (ClinicalTrials.gov Identifiers: NCT02556736, NCT03326336) have been taken.