Advancements in Retinitis Pigmentosa: The Path Toward Personalized Treatment and Vision Restoration

Retinitis pigmentosa (RP) and Age-Related Macular Degeneration (AMD) are similar in that both result in photoreceptor degeneration leading to permanent progressive vision loss. This affords the possibility of implementing vision restoration techniques, where light signaling is restored to spared retinal circuitry to recreate vision. There are far more AMD patients (Wong et al., 2014), yet more resources have been put towards researching and developing vision restoration strategies for RP despite it rarity, because of the tractability of RP disease models. The hope is that these therapies will extend to the AMD population, however, many questions remain about how the implementation of prosthetic or optogenetic vision restoration technologies will translate between RP and AMD patients. In this review, we discuss the difference and similarities of RP and AMD with a focus on aspects expected to impact vision restoration strategies, and we identify key gaps in knowledge needed to further improve vision restoration technologies for a broad patient population.

Diagnosis and measurement of progression in retinitis pigmentosa (RP) and other retinal dystrophies has relied on visual function, electrical activity and structural imaging. We propose that metabolic imaging may add a new dimension to the measurement of progression of retinal dystrophies. Retinal cell death and atrophy reduces oxygen consumption and this is measurable through retinal oximetry. The monitoring of disease progression in retinal degenerations like RP has always been complex. Funduscopy does not provide anything more than a hint of major changes occurring over time in the tissue. Electrophysiological measures such as the Ganzfeld flash electroretinogram (ERG) are useful for diagnosis, in particular of RP, but very early in the disease the ERG response may be completely flat, even when funduscopic changes are not yet manifest, and visual acuity may still be normal. It has been claimed that anyone that has a normal ERG after the age of 6 years is not likely to have RP later in life (Berson 1993). When patients manifest a flat ERG, that technique is almost useless to monitor progression, although attempts have been made to use specific ERG techniques such as discreet Fourier transform analysis of the full-field 30 Hz flicker ERG response to monitor cone function in RP (Sieving et al. 1998; Ayton et al. 2014). The multifocal electroretinogram (mfERG) is another technique that does measure remaining light responses in RP, after the flash ERG response is flat, but it primarily measures the function of remaining cones, and this central response varies greatly between patients (Jánáky et al. 2007). Peripheral visual field loss also varies between patients with RP (Iijima 2013), but perimetry is one of the methods that have proven most useful in monitoring the functional changes and progression in RP, although test–retest variability may be significant (Bittner et al. 2011). Both the mfERG and perimetry are hampered by the severe vision loss of patients with RP, and sometimes uncontrolled eye movements, as the reliability of these measures is dependent on the patient maintaining good fixation. The thickness of retinal layers can be assessed with optical coherence tomography (OCT). In particular, the IS/OS line on the OCT, and the presence and extent of the outer nuclear layer, has been found to be related to visual function (Sandberg et al. 2005; Chen et al. 2012). However, the presence of outer nuclear layer in OCT does not mean that there is visual function or evidence of photoreceptor function; conversely, there may be evidence of remaining visual function even if there is lack of structural evidence for the outer nuclear layer (Ayton et al. 2014). Thus, it may be that a multimodal assessment of both retinal structure and function in patients with a combination of methods is the way to go forward. Given the recent attempts at visual restoration in retinal degenerative diseases, and in some cases attempts to slow the progression of the disease, it is imperative to have available reliable and accurate methods to assess retinal structure and function, and even subtle changes that may occur in either direction. Most of the methods used until now have involved psychophysical and electrophysiological measures, which are dependent on photoreceptor responses to light, and structural imaging of the retina. Perhaps it might be feasible to add measures that address other aspects of retinal physiology than the ones that involve responses to light stimuli. One important process in retinal physiology is oxygen metabolism, given the extremely high retinal oxygen consumption, and recent techniques that allow for automatic and direct, non-invasive measurements of retinal vascular oxygen saturation (Beach et al. 1999; Hardarson et al. 2006; Hammer et al. 2008; Geirsdottir et al. 2012). Retinal oximetry has been developed further over the last few years, and there is considerable evidence now showing that these techniques are sensitive to the changes that occur in oxygen metabolism in ischaemic as well as degenerative retinal diseases. Repeatability of the technique has been demonstrated in both healthy eyes and in patients with either inherited retinal diseases or glaucoma (Geirsdottir et al. 2012; Turksever et al. 2015). In degenerative diseases, oxygen consumption of the retina will decrease. This will be reflected as increased saturation in retinal venules and/or decreased blood flow and vessel diameter. Estimates of oxygen extraction from the retinal vasculature could be used as a marker for progression of degenerative diseases. In glaucoma, for example, the narrowing of visual fields and decrease in retinal nerve fibre layer thickness correlate with increased venous oxygen saturation and decreased arteriovenous difference. This suggests that oximetry can be used to follow the progression of degeneration in glaucoma (Olafsdottir et al. 2011; Vandewalle et al. 2014). In exudative age-related macular degeneration, there is preliminary evidence for an increase in retinal venous oxygen saturation (Geirsdottir et al. 2014). In RP, the results are somewhat similar to results in glaucoma. Venous oxygen saturation is increased, vessel diameter is decreased (Eysteinsson et al. 2014), and the arteriovenous difference is decreased with reduced retinal thickness (Turksever et al. 2014; Ueda-Consolvo et al. 2015). Increased retinal venous oxygen saturation has also been found in rod–cone dystrophy, while the saturation appears to be less affected in cone–rod dystrophy and inherited maculopathies (Todorova et al. 2014). The studies with retinal oximetry in RP involve a low number of patients with a fairly advanced disease, but they suggest that this technique may provide additional information about the progression of the disease that hitherto has not been available, and possibly be more sensitive, reliable and robust for that purpose than most of the ones discussed above. Its reliability is not dependent on the ability of the patient to control eye movements or fixate on a target for an extensive period of time. Retinal oximetry has a well-established test–retest reliability that is equal to or superior to for instance the mfERG or visual field testing. However, a larger cohort of patients, with different stages of the disease, would need to be examined with retinal oximetry in order to evaluate its sensitivity to the changes that occur during progression of the disease. Longitudinal studies of similar cohorts with retinal oximetry could provide additional information about the time–course of the changes. We consider it likely that retinal oximetry, which provides indication of cell death or conversely increased oxygen consumption when treatment increases the viability of cells, may turn out to be a valuable addition to a multimodal assessment of disease progression, and no less importantly the success or failure of any treatment of retinal degenerations like RP. In fact, it may turn out to be one of the most reliable and sensitive methods available to measure progression of RP and other retinal degenerative diseases, and the effectiveness of treatment.

Vision restoration is an ideal medical application for optogenetics, because the eye provides direct optical access to the retina for stimulation. Optogenetic therapy could be used for diseases involving photoreceptor degeneration, such as retinitis pigmentosa or age-related macular degeneration. We describe here the selection, in non-human primates, of a specific optogenetic construct currently tested in a clinical trial. We used the microbial opsin ChrimsonR, and showed that the AAV2.7m8 vector had a higher transfection efficiency than AAV2 in retinal ganglion cells (RGCs) and that ChrimsonR fused to tdTomato (ChR-tdT) was expressed more efficiently than ChrimsonR. Light at 600 nm activated RGCs transfected with AAV2.7m8 ChR-tdT, from an irradiance of 1015 photons.cm−2.s−1. Vector doses of 5 × 1010 and 5 × 1011 vg/eye transfected up to 7000 RGCs/mm2 in the perifovea, with no significant immune reaction. We recorded RGC responses from a stimulus duration of 1 ms upwards. When using the recorded activity to decode stimulus information, we obtained an estimated visual acuity of 20/249, above the level of legal blindness (20/400). These results lay the groundwork for the ongoing clinical trial with the AAV2.7m8 - ChR-tdT vector for vision restoration in patients with retinitis pigmentosa.

Transorbital electrical stimulation in retinitis pigmentosa. Better results joining visual pattern stimulation?

Resting-state functional connectivity (rsFC) has been used to assess the effect of vision loss on brain plasticity. With the emergence of vision restoration therapies, rsFC analysis provides a means to assess the functional changes following sight restoration. Our study demonstrates a partial reversal of blindness-induced rsFC changes in Argus II retinal prosthesis patients compared to those with severe retinitis pigmentosa (RP). For 10 healthy control (HC), 10 RP, and 7 Argus II subjects, four runs of resting-state functional magnetic resonance imaging (fMRI) per subject were included in our study. rsFC maps were created with the primary visual cortex (V1) as the seed. The rsFC group contrast maps for RP > HC, Argus II > RP, and Argus II > HC revealed regions in the post-central gyrus (PostCG) with significant reduction, significant enhancement, and no significant changes in rsFC to V1 for the three contrasts, respectively. These findings were also confirmed by the respective V1-PostCG ROI-ROI analyses between test groups. Finally, the extent of significant rsFC to V1 in the PostCG region was 5,961 in HC, 0 in RP, and 842 mm3 in Argus II groups. Our results showed a reduction of visual-somatosensory rsFC following blindness, consistent with previous findings. This connectivity was enhanced following sight recovery with Argus II, representing a reversal of changes in cross-modal functional plasticity as manifested during rest, despite the rudimentary vision obtained by Argus II patients. Future investigation with a larger number of test subjects into this rare condition can further unveil the profound ability of our brain to reorganize in response to vision restoration.

Channelrhodopsins, the directly light‐gated ion channels from green algae, provide a powerful tool for basic research in neuroscience as well as potential applications for treating neurological diseases and disorders. One of the promising clinical applications is to cure blindness caused by the death of rod and cone photoreceptors. Retinitis pigmentosa ( RP ) is one of diseases that causes blindness. Although photoreceptor cells are degenerated in the retina of RP patients, other retinal neurons such as retinal ganglion cells and on bipolar cells still survive. Owing to the inherent characteristics of chlamydomonas‐derived channelrhodopsin‐2 ( ChR2 ), photosensitive neurons can be produced in the retina by the transfer of the ChR2 gene into survived retinal neurons. A single injection of a virus vector into the eye can achieve the vision restoration in rodent model that will be a useful treatment for the patients with blindness. Herein, we introduce the molecular properties of ChR2 and a potential as a new strategy for restoring vision in humans. Key Concepts Channelrhodopsins, microbial retinal binding proteins, transiently induce photo currents by light stimuli. Photocycle of channelrhodopsins remains preserved when they are heterologously expressed in animal and human cells. Channelrhodoposins functions as a directly light‐gated cation channels with million second activation and deactivation kinetics. Artificial photoreceptor cells can be produced in various types of animal neurons by transducing a single gene. Converting surviving inner retinal neurons into directly photosensitive cells is a new strategy to treating blindness after the death of rod and cone photoreceptors. Using delivery by adeno‐associated viral vectors, long‐term expression of channelrhodopsin‐2 can be achieved in rodent inner retinal neurons in vivo . ChR2 can be expressed without immunologically harmful reactions in vivo .

Visual prosthesis : Artificial vision

Photopharmacology has yielded compounds that have potential to restore impaired visual responses resulting from outer retinal degeneration diseases such as retinitis pigmentosa. Here we evaluate two photoswitchable azobenzene ion channel blockers, DAQ and DAA for vision restoration. DAQ exerts its effect primarily on RGCs, whereas DAA induces light-dependent spiking primarily through amacrine cell activation. Degeneration-induced local field potentials remain a major challenge common to all vision restoration approaches. These 5–10 Hz rhythmic potentials increase the background firing rate of retinal ganglion cells (RGCs) and overlay the stimulated response, thereby reducing signal-to-noise ratio. Along with the bipolar cell-selective photoswitch DAD and second-generation RGC-targeting photoswitch PhENAQ, we investigated the effects of DAA and DAQ on rhythmic local field potentials (LFPs) occurring in the degenerating retina. We found that photoswitches targeting neurons upstream of RGCs, DAA (amacrine cells) and DAD (bipolar cells) suppress the frequency of LFPs, while DAQ and PhENAQ (RGCs) had negligible effects on frequency or spectral power of LFPs. Taken together, these results demonstrate remarkable diversity of cell-type specificity of photoswitchable channel blockers in the retina and suggest that specific compounds may counter rhythmic LFPs to produce superior signal-to-noise characteristics in vision restoration.

Subtenon Implantation of Wharton’s Jelly Derived Mesenchymal Stromal Cell for Retinitis Pigmentosa: A 1 – 2 Year Follow-Up Report

Introduction: Retinitis pigmentosa (RP) is an inherited retinal disorder, characterized by photoreceptor degeneration inducing progressive vision loss. This study evaluates its impact on quality of life (QOL) and emotional states of patients affected by RP. Methods: A cross-sectional study was conducted on 60 RP patients diagnosed with rod-cone dystrophy and on 20 control subjects. The RP population has been divided into 3 groups according to visual field (VF) and visual acuity (VA) impairments. Concurrently, scores of self-reported QOL (25-item National Eye Institute Visual Functioning Questionnaire) and of the Hospital Anxiety and Depression Scale for anxiety/depression assessments were collected. Results: For the QOL composite score, we noticed consistent differences between all VF and VA affected groups and their control group. We also found significant differences between both the most affected VF group (VF1: ØVF <20°) and VA group (VA1: VA <0.3) compared to other VF and VA groups. For anxiety/depression scores, consistent differences have been found between the control group and VF1 and VA1, respectively. Conclusions: This work determines that, for RP patients, a significant QOL and emotional state deterioration correlates with a residual VF diameter below 20° and a VA lower than 0.3. It introduces, for the first time, thresholds to be used in visual restoration or visual preservation therapies to improve QOL of RP patients.

Stimulation of retinal neuronal cells using optogenetics via use of chanelrhodopsin-2 (ChR2) and blue light has opened up a new direction for restoration of vision with respect to treatment of <i>Retinitis pigmentosa </i>(RP). In addition to delivery of ChR2 to specific retinal layer using genetic engineering, threshold level of blue light needs to be delivered onto the retina for generating action potential and successful behavioral outcome. We report measurement of intensity distribution of light reaching the retina of Retinitis pigmentosa (RP) mouse models and compared those results with theoretical simulations of light propagation in eye. The parameters for the stimulating source positioning in front of eye was determined for optimal light delivery to the retina. In contrast to earlier viral method based delivery of ChR2 onto retinal ganglion cells, in-vivo electroporation method was employed for retina-transfection of RP mice. The behavioral improvement in mice with Thy1-ChR2-YFP transfected retina, expressing ChR2 in retinal ganglion cells, was found to correlate with stimulation intensity.

Key optogenetic advances in retinal prostheses: A comparative narrative review.

Retinal degenerations, such as age-related macular degeneration and retinitis pigmentosa, present significant challenges due to genetic heterogeneity, limited therapeutic options, and the progressive loss of photoreceptors in advanced stages. These challenges are compounded by difficulties in precisely targeting residual retinal neurons and ensuring the sustained efficacy of interventions. Optogenetics offers a novel approach to vision restoration by inducing light sensitivity in residual retinal neurons through gene delivery of light-sensitive opsins. This review traces the evolution of opsins in optogenetic therapies, highlighting advancements from early research on channelrhodopsin-2 (ChR2) to engineered variants addressing key limitations. Red-shifted opsins, including ReaChR and ChrimsonR, reduced phototoxicity by enabling activation under longer wavelengths, while Chronos introduced superior temporal kinetics for dynamic visual tracking. Further innovations, such as Multi-Characteristic Opsin 1 (MCO1), optimized opsin performance under ambient light, bridging the gap to real-world applications. Key milestones include the first partial vision restoration in a human patient using ChrimsonR with light-amplifying goggles and ongoing clinical trials exploring the efficacy of opsin-based therapies for advanced retinal degeneration. While significant progress has been made, challenges remain in achieving sufficient light sensitivity for functional vision under normal ambient lighting conditions in a manner that is both effective and safe, eliminating the need for external light-enhancing devices. As research progresses, optogenetic therapies are positioned to redefine the management of retinal degenerative diseases, offering new hope for millions affected by vision loss.

Optogenetic strategies for vision restoration involve photosensitizing surviving retinal neurons following retinal degeneration, using emerging optogenetic techniques. This approach opens the door to a minimally-invasive retinal vision restoration approach. Moreover, light stimulation has the potential to offer better spatial and temporal resolution than conventional retinal electrical prosthetics. Although proof-of-concept studies in animal models have demonstrated the possibility of restoring vision using optogenetic techniques, and initial clinical trials are underway, there are still hurdles to pass before such an approach restores naturalistic vision in humans. One limitation is the development of light stimulation devices to activate optogenetic channels in the retina. Here we review recent progress in the design and implementation of optogenetic stimulation devices and outline the corresponding technological challenges. Finally, while most work to date has focused on providing therapy to patients suffering from retinitis pigmentosa, we provide additional insights into strategies for applying optogenetic vision restoration to patients suffering from age-related macular degeneration.

For the prosthetic retina, a device replacing dysfunctional cones and rods, with the ability to mimic the spectral response properties of these photoreceptors and provide electrical stimulation signals to activate residual visual pathways, can relay sufficient data to the brain for interpretation as color vision. Organic semiconductors including conjugated polymers with four different bandgaps providing wavelength‐specific electrical responses are ideal candidates for potential full‐color vision restoration. Here, conjugated polymer photocapacitor devices immersed in electrolyte are demonstrated to elicit a photovoltage measured by a Ag/AgCl electrode 100 microns from the device of ≈−40 mV for 15–39 µW mm−2 of incident light power density at three wavelengths: 405 nm for blue photoreceptor candidate material, 534 nm for green, 634 nm for red. Photoresponse is substantially improved by introducing polymer donor/acceptor molecules bulk heterojunctions. Devices with bulk heterojunction configurations achieved at least −70 mV for green candidates with the highest at −200 mV for red cone candidates. These findings highlight the potential for organic materials to bridge the gap toward natural vision restoration for retinal dystrophic conditions such as age‐related macular degeneration, Stargardt disease, or retinitis pigmentosa and contribute to the ongoing advancements in visual prosthetic devices.