In macular dystrophies, similarly to numerous inherited retinal degenerative diseases, parts of the inner retina survive, even after complete degeneration of the retinal photosensitive layer, and remain responsive to electrical stimulation. Retinal prosthesis uses this morphological paradigm to activate the remaining inner retinal network and to restore visual function. Different groups worldwide are currently working on retinal implant devices. The most important clinical follow-up data today are reported for the epiretinal implant Argus II (Second Sight Medical Products, Sylmar, California, United States). This device is surgically positioned on the surface of the retina to communicate directly with the ganglion and bipolar cells. It receives light signals from an external camera system that includes a video real-time processing unit (Fig. 11.2). These signals are transmitted wirelessly to an antenna in the implant and then to the 60-electrode array to send information to the brain via the optic nerve. Long-term results of multicenter clinical study demonstrated that fitted with Argus II patients with profound visual loss (29 subjects with retinitis pigmentosa and one with choroideremia) performed better on visual tasks, including object localization, motion and oriented grating discrimination, identification of letters and words, and even reading short sentences [65, 66]. Argus II can also simulate visual braille as a sensory substitute for reading [67]. Argus II received the commercial use approval of the European regulators (2011) and the US Food and Drug Administration (2013) for patients with profound visual loss.

An innovative vision restoration system, IRIS® (Pixium Vision SA, France), is currently being tested in several centers in Europe (ClinicalTrials.gov: NCT01864486). IRIS® is an epiretinal system that consists of three technical components: an implant (with an array of approximately 50 electrodes), a visual interface, and a pocket computer.

Subretinal implants are positioned in close proximity to the surviving neurons in the visual pathway (between the retina and the choroids) and receive light directly from the environment [68]. In theory, this approach may offer better inherent mechanical stability and may possibly require less current for effective stimulation, but it remains challenging from a surgical point of view. Clinical trial data (NCT01024803) obtained with the subretinal device made by Retina Implant AG, Germany, (the wirelessly powered subretinal implant Alpha IMS) in profoundly blind patients with retinitis pigmentosa demonstrated stable visual percepts, restoration of useful vision in daily life, and even identification of objects and letters [69, 70]. The Retina Implant AG subretinal implant technology received CE marking in 2013. Despite the much larger number of pixels (1,500), however, the resulting visual acuity was similar to the 60-electrode Argus II implant (approximately 20/1200).

Researchers at Stanford University are currently developing with Pixium Vision a wirelessly powered photovoltaic prosthesis [71] in which each pixel of the subretinal array directly converts patterned pulsed near-infrared light projected from video goggles into local electric current to stimulate the nearby retinal neurons. Full integration of the photovoltaic retinal prosthesis and high-resolution stimulation of the RGC have been demonstrated in normal and degenerate (RCS) rat retinas [72]. Implants with pixel sizes of 280, 140, and 70 μm implanted in the subretinal space in normal and RCS rats were able to elicit robust cortical responses upon stimulation with pulsed near-infrared light [73], providing evidence that the visual information generated by the implant in the retina arrives at the visual cortex. Several advantageous features—the surgical procedure appears simple, all pixels function independently, the external camera operates over a wide range of ambient illumination, and the natural link between eye movements and image perception is preserved—make the photovoltaic prosthesis promising for vision restoration in retinal degenerative diseases.

Despite the great technical progress, the quality of the images achieved with retinal prosthetic devices remains a challenge. New electrode designs and new materials aiming at improving visual resolution and safety profiles are currently under investigation.

Optogenetics combines genetic strategies to target light-sensitive proteins within the cells and optical stimulation to activate these selectively targeted proteins. For vision restoration, optogenetics aims at converting strategically important retinal cell types into “artificial photoreceptors.” This is possible, first, because many cone photoreceptors survive even in advanced stages of retinal disease and maintain their cell body for extended periods of time [74, 75] and, second, because of the discovery of genes that inserted into cells encode membrane proteins responsive to light and able to turn the neurons ON or OFF [76, 77]. Several groups have demonstrated that spared inner retinal neurons are sensitized to light using channelrhodopsin-2 (ChR2), a microbial-type rhodopsin found in the green algae Chlamydomonas reinhardtii [78, 79], and halorhodopsin (NpHR), an archaebacterial protein from Natronomonas pharaonis [80] (Fig. 11.3).

ChR2 delivered by rAAV was shown to establish targeted, robust, and long-term transgene expression in ON bipolar cells of the retina, leading to electrophysiological and behavioral improvements in visual function in animal models of blindness; rd1, rd10, and rd16 mouse models [81–83]; and RCS rat [84]. Recent studies have shown that NpHR introduced to surviving cone cell bodies in two mouse models of retinitis pigmentosa (RP) reactivated retinal ON and OFF pathways, as well as the retinal circuitry, and enabled RP mice to perform visually guided behaviors [85]. Moreover, NpHR targeted to human postmortem photoreceptors with no measurable intrinsic rod- or cone-mediated photosensitivity restored light responses in photoreceptor cells, clearly demonstrating that reactivation of the surviving retinal structures and phototransduction cascade required for vision is possible [85]. These preclinical data hold promise that legally blind or severely visually impaired patients with no visual field, but with a preserved layer of cone bodies (visible on optical coherent tomography), could be eligible for optogenetic functional restoration of cones.

Optogenetic stimulation of the remaining RGCs or bipolar cells in retinal degenerative disorders provides an alternative approach to vision restoration. Optogenetics has some advantages, including minimally invasive neuronal stimulation, independence of the nature of the retinal degeneration, and resemblance of the artificially stimulated retinal activity to the normal activity of retinal circuits. Different strategies for optogenetic vision restoration, including their advantages and possible combination with other methods to slow retinal degeneration and/or restore vision, were recently reviewed [7].

Transplantation of retinal cells or photoreceptor precursor cells is another potential strategy to restore vision in patients with macular dystrophies. At present, the most promising options considered for retinal transplantations are embryonic stem cells (ESCs) that can be isolated from developing embryos and induced pluripotent stem cells (iPSCs) that can be generated from adult differentiated somatic cells, e.g., fibroblasts, via overexpression of a set of transcription factors Oct4, Sox2, Klf4, and c-Myc [86]. Initial data demonstrated that transplanted progenitor or precursor cells isolated at the correct ontogenetic stage from the developing retina can integrate into the host retina and differentiate into rod photoreceptors [87].

Recent findings confirmed the survival and differentiation of some photoreceptors derived from three-dimensional ESC cultures: ESC-derived photoreceptor cell precursors were able to integrate and mature and to form outer segments and some synaptic connections after transplantation into the degenerate adult mouse retina [88]. Whether similar integration and functional improvement can be achieved using human cells remains to be established. In all cases, translation to clinical studies will require validated disease models, robust methods, and standardized protocols to control cell maturation and cell fate specification and relevant cell-manufacturing strategies. A recent study reported in vitro recreation of key structural and functional features of the native retina, in particular the presence of photoreceptors with outer segment disks and photosensitivity [89]. An innovative approach to produce retinal cells for regenerative medicine and drug-screening purposes was recently proposed [90]. It is based on confluent human iPSC, bypassing embryoid body formation and the use of exogenous molecules, coating, or Matrigel. This new retinal differentiation process allows simultaneous generation of both RPE cells and self-forming neural retina-like structures containing retinal progenitor cells (RPCs) within 2 weeks. When switched to floating cultures, structures containing RPCs can differentiate into all retinal cell types, including RGCs and precursors of photoreceptors, needed for therapeutic applications.

The main advantages of cell therapies as a source for regenerative therapy is that: (1) they are gene-independent, thus applicable to a broad range of retinal diseases, and (2) can be expanded indefinitely in culture and used as an unlimited source of retinal cells for treatment of retinal degenerative diseases. The first ever safety and tolerability prospective clinical trial to evaluate subretinal injection of hESC-derived RPE cells in patients with advanced dry AMD and Stargardt macular dystrophy is currently under way (ClinicalTrials.gov: NCT01344993; NCT01345006). Very early results suggest graft survival, biological activity, and no major safety concern (no signs of hyperproliferation, tumorigenicity, ectopic tissue formation, or apparent rejection after 4 months) [91, 92]. As hiPSCs can be obtained directly from the patient, they have the advantage of being autologous and therefore less immunogenic. Retinal cells derived from hiPSCs have been generated by different laboratories worldwide, and some groups are currently setting up human clinical trials with hiPSC-derived RPE for treatment of AMD, e.g., pilot clinical study to assess the safety and feasibility of the transplantation of autologous iPSCs in patients with exudative AMD started in Japan in 2013 [93]. There is no safety report so far. Recently, this pioneering clinical study has been suspended with the decision of the RIKEN Center for Developmental Biology not to treat the second patient [94]. Advances in research into iPSC applications for treatment of retinal degeneration were recently reviewed in detail by Cramer and MacLaren [95–97].

Technologies transforming auditory or tactile information into visual sensory information are currently under clinical evaluation. Using a visual-to-auditory sensory substitution device called “The vOICe”, blind and blindfolded participants were able to locate and identify objects through images encoded by sound [98, 99]. Even congenitally fully blind adults could be taught to read and recognize complex images using “soundscapes,” sounds topographically representing images [100, 101]. A device that translates information from a digital video camera to the tongue, BrainPort®, helps blind individuals to recognize high-contrast objects, their location and movement, and some aspects of perspective and depth [102]. Sensory substitution devices are noninvasive and cheap and usually require training in a scale of hours [101]. By providing a visual-like experience, they can compensate for some effects of early or lifelong blindness and serve as aids in daily visual tasks.

Identifying patients who can benefit from these emerging therapeutic strategies is crucial for selecting appropriate therapy. High-resolution imaging techniques (e.g., optical coherence tomography and adaptive optics) and functional studies (e.g., microperimetry) are essential for patient selection and establishing the benefit of these novel therapies. Standardized mobility and task-related tests are needed for assessment of the subjective visual handicap and for a reliable evaluation of the actual benefit for the patient. Development of new rehabilitation programs and devices, especially those that take advantage of visual plasticity (persisting even in old age), should be of paramount importance. Novel nanosized materials and systems developed in recent years provide novel tools for drug, gene, and trophic factor delivery in ophthalmology and offer, in principle, low risk of immunogenicity, high transfection efficiency, relatively low cost, and, possibly, greater ease of production compared with viral vectors. In addition, they can accommodate large genes, unlike traditional viral vectors. Recent papers have reviewed nonviral vectors and nanotechnology for vision restoration [103, 104].

Further investigations on genetics and genotype-phenotype correlations would unravel new insights into disease causes and specific therapeutic targets for macular dystrophies. Despite the improved vision after RPE65 gene augmentation therapy, photoreceptor degeneration was shown to progress both in the canine model and in humans [17, 18]. These findings emphasize the need of (1) slowing the retinal degeneration process in long term, in addition to improving the retinal function, and (2) evaluation of combination therapies in the treatment of retinal dystrophies [17]. What would be particularly important is to transfer the knowledge of rare macular dystrophies toward generation of effective therapies that could potentially be applicable in very common macular diseases such as AMD.