Restoring Vision to the Blind: Introduction.

The notion that restoring vision to the blind is possible has long been thought to be fanciful. However, beginning as far back as the 1960s vision scientists began to investigate the possibility of restoring vision to the blind by activating neurons in the visual pathways beyond the eye, namely in the visual cortex. These early experiments showed that it is possible to elicit visual sensations in humans by electrically stimulating neurons in the visual cortex. Most blindness is caused by defects in the eye. It can be caused first of all by damage to the optical pathways that are required for the focusing of a sharp image on the light-sensitive retinal photoreceptors that line the back of the eye. Today, it is generally possible to cure these optical impediments. Cataract surgery to remove an opaque lens and replace it with an artificial lens is carried out routinely in many parts of the world, and corneal transplants with natural or artificial corneas are generally successful. It should be noted, however, that in those parts of the world where such procedures are not available, blindness remains common because of such defects. It is estimated that there may be as many as 20 million blind people in the world because of cataracts. The major cause of untreatable blindness throughout much of the world today is retinal degenerative disease, most often because of a loss of photoreceptor cells but also, especially in glaucoma, a loss of third order neurons of the retina, the retinal ganglion cells whose axons form the optic nerve and carry the visual signal from the eye to the higher visual centers such as the cortex. Because most retinal degenerations cause blindness by destroying the photoreceptors, much emphasis in the quest to cure blindness is to restore photoreceptive function in the blind eyes, or to substitute for the loss of photoreceptor function. Most success so far has come from two approaches. First, retinal prostheses have been developed that electrically stimulate the second or third order retinal neurons, namely the retinal bipolar or ganglion cells. Indeed, two types of prostheses have been successfully implanted in blind human patients and have restored light sensitivity and low-acuity vision to the patients. The second approach has been successful for patients with specific gene defects that severely compromise photoreceptor function, and the treatment consists of injecting a viral construct containing the normal gene into the eye, thus replacing the defective gene. Again, substantial improvement in vision, especially light sensitivity, has been demonstrated in these patients. A newer approach, not yet tested in humans but which soon will be, is in essence a combination of the above two approaches, namely imparting light sensitivity to retinal neurons via genetic means called optogenetics. Genes that code for light-sensitive molecules linked to an ion channel or pump are introduced into various retinal cells, most often bipolar or ganglion cells. In animals treated this way, the treated cells are stimulated by light, causing the opening of ion channels or activating ion pumps, both of which permit ions to flow across the cell outer membranes, thus electrically activating them. This technique was recently applied in blind animals with some remaining cone cells, but which had lost light sensitivity because the outer segments of the cells (which contain the light-sensitive molecules—the visual pigments) had degenerated. Once light sensitivity was restored to these cones, downstream retinal pathways could be activated and the animals showed visual behavioral responses. Another approach to replace damaged or destroyed photoreceptor cells is to transplant healthy photoreceptor cells into the eyes of blind animals. This strategy has had limited success so far—the number of transplanted cells that survive and integrate into the retinal circuitry is quite limited—but some restoration of electrical activity recorded from the eyes occurs and the animals do show some behavioral responses to light. Stem cells, which in theory can differentiate into any cell type, have also been introduced into blind eyes, including some human eyes, again with very limited and largely undocumented success. Investigators are now inducing stem cells maintained in culture to differentiate into photoreceptor cells and then are injecting such cells into eyes whose photoreceptor cells have degenerated; this approach appears promising and may be more successful. In addition to direct deleterious effects of a disease process or gene defect in the photoreceptor cells themselves, such defects can also occur in the associated retinal pigment epithelial cells, and this can cause photoreceptor death. The photoreceptor cells and overlying retinal pigment epithelium are intimately connected, and they depend upon each other to function. The isomerization of vitamin A, to generate the 11-cis retinoid molecule needed to regenerate the visual