'Prosthetic' retinal cells let blind mice see light

In an experiment that could offer a new pathway to restoring vision in people with inherited retinal degeneration, researchers have engineered cells in the eye to be light sensitive that were not before. Using a harmless virus, they introduced a gene for a light-sensitive protein into "inner retinal neurons" in a strain of mice with photoreceptor deficiency that resembles the defect in such inherited human disorders as retinitis pigmentosa. Unlike the retinal rods and cones that normally function as light-sensing cells in the eye, these retinal neurons are normally not photosensitive. The light-sensitive protein they used, called channelrhodopsin-2 (ChR2), is found in green algae.

As reported in the April 6, 2006 issue of Neuron, Zhuo-Hua Pan of Wayne State University School of Medicine and colleagues found that the introduced protein rendered the retinal neurons sensitive to light. What's more, they found, the protein persisted for long periods in the neurons, and the neurons generated signals that were transmitted to the visual cortex of the animals' brains.

"With this strategy, the investigators have made a paradigm shift in the field and opened the possibility of genetically modifying the surviving retinal interneurons to function as a replacement light-sensing receptor," wrote John Flannery and Kenneth Greenberg in a preview of the paper in the same issue of Neuron. "This publication is clearly a significant first step into this new field of re-engineering retinal interneurons as genetically modified 'prosthetic' cells," they wrote.

Pan and his colleagues cautioned that far more research must be done to determine whether their genetic engineering approach can be applied to restore vision in humans with inherited retinal degeneration disorders. For one thing, they said, they have not yet determined whether the light signals reaching the visual cortex could be interpreted as vision. Also, the algal protein is less sensitive to light than is the normal light-detecting protein in the eye.

Finally, they wrote, it remains unclear which of the many inherited retinal diseases might be treatable by using the technique. "The remodeling of inner retinal neurons triggered by photoreceptor degeneration has raised some concerns for the retinal-based rescue strategy after the death of photoreceptors," wrote Pan and colleagues. "However, retinal degenerative diseases are heterogeneous as to the time course of the degeneration, survival cell types, and, possibly, their functional state. Therefore, further studies are required to evaluate what types of retinal degenerative diseases and/or what disease stages are suitable for this potential treatment strategy," they wrote.

However, noted the researchers, their technique avoids some problems presented by other approaches to restoring vision in such diseases. These approaches include transplantation of normal photoreceptor cells into the eye or implantation of electronic retinal "chips" to replace the photoreceptor function.

"An important advantage of the strategy sought in this study is that it does not involve the introduction of tissues or devices into the retina and, therefore, may largely avoid the complications of immune reactions and biocompability," wrote the researchers. "In addition, it could potentially achieve high spatial resolution for the restored 'vision' because the approach targets the cellular level. Thus, the expression of microbial-type channelrhodopsins, such as ChR2, in surviving retinal neurons may be another potential strategy for the treatment of complete blindness caused by rod and cone degeneration," they wrote.

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The researchers include Anding Bi, Jinjuan Cui, Yu-Ping Ma, and Zhuo-Hua Pan of Wayne State University School of Medicine in Detroit, MI; Alexander M. Dizhoor of Wayne State University School of Medicine in Detroit, MI and the Pennsylvania College of Optometry in Elkins Park, PA; Elena Olshevskaya of the Pennsylvania College of Optometry in Elkins Park, PA; Mingliang Pu of Peking University in Beijing, China. This work was supported by National Institutes of Health grants EY12180 and EY16087 to Z.-H.P., EY11522 and Pennsylvania Department of Health to A.M.D., and core grant EY04068 to Department of Anatomy and Cell Biology at Wayne State University.

Bi et al.: "Ectopic Expression of A Microbial-Type Rhodopsin Restores Visual Responses in Mice with Photoreceptor Degeneration." Publishing in Neuron 50, 23-33, April 6, 2006. DOI 10.1016/j.neuron.2006.02.026 www.neuron.org


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