Gene therapy meets cell therapy in the fight for sight

In the eye, a tiny pit in the central retina provides us the clearest vision of all. This region contains the highest number of cone photoreceptors – responsible for our daylight, high acuity vision. Unfortunately, several diseases lead to the degeneration of these photoreceptor cells.

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Diseases like macular degeneration, affect 30 million – mostly elderly people worldwide whereas inherited retinal degenerations like retinitis pigmentosa (RP) cause 1.5 million people to become legally blind by the age of 40. Since vision loss is one of the most feared handicaps, there are intensive efforts to find solutions to these diseases that would allow patients to recover vision- especially high-acuity vision. The field of ophthalmology is thus an incredibly fertile ground for the development of new therapies using the cutting-edge biotechnologies such as gene therapy, cell therapy and optogenetics.

The work we just published in Nature Communications leverages the power of these biotechnologies in order to help patients who have lost their photoreceptors to recover vision. Why do we need not one but several technologies? This can be attributed to the complexity of the problem we chose to address as well as to the shortcomings of each technology in their current form. Thankfully each shortcoming could be compensated by the versatility the other technology offers (see Figure and text below). The synergy between the different approaches we used in this study also initiated a great collaboration between the authors of the study who come from different horizons. This project, that started out as an informal discussion between Jens Duebel and Marius Ader at an ISER meeting, flourished over several years between the Paris Vision Institute and Germany. Jens Duebel’s background in optics, electrophysiology and retinal circuitry was perfectly complemented by my expertise in gene delivery and optogenetics. Marius Ader and Olivier Goureau brought in their knowledge of stem cell biology and transplantation. The compelling ideas became reality in the hands of a group of enthusiastic and hard-working postdocs, students and research assistants. 

Figure Legend: Schematic representation of the three fold challenge in photoreceptor cell replacement. In order to provide visual improvement, the transplanted photoreceptors need to form functional outer segments (OS), maintain light sensitivity, and develop connections with the host bipolar cells (BPC) for signal transmission. Optogenetics restores light sensitivity in the second or third order neurons of the retina loses information processing of the inner retina. Transplanted photoreceptors fail to develop normal OS structure and lack light sensitivity. Introduction of a hyperpolarizing microbial opsin into the photoreceptor derivatives before transplantation provides a novel approach for vision restoration in late stage retinal degeneration. RPE- retinal pigment epithelium; PR- photoreceptor; BPC- Bipolar cells.

Initially optogenetics has been proposed to restore light sensitivity in patients suffering from photoreceptor cell loss. Optogenetic approaches use viral vectors to deliver opsins to remaining retinal cells (i.e. gene therapy) – they commonly target second and third order neurons downstream from the photoreceptors that are still present in late stages of degenerative diseases. Remaining cones lacking outer segments have also been targeted but less frequently due to concerns about their longevity and the low percentage of patients who still have such structures. This is a bit of a conundrum: conferring light sensitivity to cells downstream from photoreceptors, bypasses the important information processing normally conducted by the inner retinal circuitry. On the other hand, rescuing the function of remaining ‘dormant’ cones can only be useful in a minor portion of late stage RP patients. Cell therapy offers the possibility of replacing the dying photoreceptors with new ones, which would circumvent both shortcomings, but there there’s another hurdle: the difficulty in inducing the grafted cells to grow and maintain light-sensitive outer segments (containing the opsins that capture light)…. 

Today, we can generate high numbers of replacement photoreceptors from human induced pluripotent stem cells and in their differentiated forms; these cells display many hallmarks of photoreceptor cell identity. Helas!.. They have a very difficult time forming the delicate and metabolically demanding outer segments. What more? Such structures need to be phagocytized and regenerated continuously for phototransduction to occur. This brings in an additional layer of complexity, requiring interplay between non-neuronal cells and the photoreceptors. 

Needless to say, without such light capturing antenna (outer segment), there is little utility to grafting new photoreceptors into a blind subject’s retina. For a cell therapy approach that is independent from the formation and maintenance of the outer segments, we turned to optogenetics: a technique that uses rudimentary one-component microbial opsins to render any neuron sensitive to light. Microbial opsins do not require any cascade or chromophore replenishment. We introduced one such hyperpolarizing microbial opsin into photoreceptor precursors from new-born mice or into cone photoreceptors from human induced pluripotent stem cells. After transplantation into blind mice, we observed light-driven responses at the retinal and behavioural levels originating from both grafts. Light responses we recorded were characteristic of the inserted microbial opsins’ properties. These results demonstrate that structural and functional retinal repair is possible by combining stem cell therapy and optogenetics. 


Deniz Dalkara

Tenured INSERM researcher, denizdalkara