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  • "Three blind mice” could find hope in optogenetics

BioPhotonics
Jul 2011
Compiled by BioPhotonics staff

CAMBRIDGE, Mass. — The fabled blind mice in the nursery rhyme could someday get their sight back if other cells of the retina — which are spared by the disease retinitis pigmentosa — can be made sensitive to light, a new study of the rodents has found.

Using a technology called optogenetics, co-invented by Edward S. Boyden of MIT, scientists at the University of Southern California in Los Angeles, with a consortium of institutions including MIT, are hopeful that the method eventually could be used to restore sight in humans. Their findings appeared online April 19, 2011, in Molecular Therapy (doi: 10.1038/mt.2011.69).


Ed Boyden, an assistant professor in MIT’s Media Lab and co-inventor of optogenetics, hopes that the technology could eventually be used to restore sight in humans. Courtesy of Dominick Reuter.


Optogenetics offers the ability to bypass damaged photoreceptors, or light-sensitive cells. It involves genetically engineering other types of cells to respond to light by adding genes that code for proteins called channelrhodopsins, which normally sit in the photoreceptor cell membrane. Those channels — activated by light — control the flow of ions into or out of the cell. When light strikes the cell, the channels open or close, either stimulating or suppressing the flow of ions and the electrical activity of the cell.

The study focused on making retinal bipolar cells sensitive to light. The investigators targeted a subset of bipolar cells called ON cells, which are activated in bright light, while OFF bipolar cells are suppressed in bright light. To ensure that the channelrhodopsin gene was expressed only in the ON cells, they included a DNA sequence that is known to drive gene expression specifically in those cells.

Having one of three different genetic mutations, all of which lead to a loss of photoreceptors by the time they reach adulthood, the blind mice were given a subretinal injection of the virus carrying the channelrhodopsin gene. The gene was selectively integrated into the ON bipolar cells.

By inducing light sensitivity in other cells of the retina, the researchers brought back enough vision for the mice to navigate a water maze that had six arms branching off from a central pool. Only one arm offered an exit, which was lit up. Sighted mice quickly navigated the maze, but the blind mice had a more difficult time. However, they eventually found their way out by trying each of the arms in turn.


Rod bipolar cells in human retina. Courtesy of retinalmicroscopy.com


“We don’t know for sure what the animals are consciously seeing, but this study indicates that the mice can make cognitive use of their visual information,” Boyden said.

At first, there was little evidence that the blind mice treated with the gene were any better off than untreated mice. After two weeks, however, the treated mice navigated the maze just as well as the sighted mice, and much better than the untreated blind mice.

The effects were observed to last up to 10 months, the length of the study, and the treatment did not provoke any sort of immune response or other adverse effects in the mice.

The researchers plan to develop new behavioral tests to determine what kind of visual input the mice are actually getting. And Boyden is screening genomes of plants and other species to look for new channelrhodopsinlike proteins that could perform even better than the ones currently in use.

With the hope of preclinical studies in the future to determine the potential therapeutic benefit for humans, the scientists might have to design optical hardware such as goggles that could transform the various light levels that a human patient might encounter in everyday life into the levels optimal for activating the light-gated channels.


GLOSSARY
optogenetics
A discipline that combines optics and genetics to enable the use of light to stimulate and control cells in living tissue, typically neurons, which have been genetically modified to respond to light. Only the cells that have been modified to include light-sensitive proteins will be under control of the light. The ability to selectively target cells gives researchers precise control. Using light to control the excitation, inhibition and signaling pathways of specific cells or groups of cells...
retina
1. The photosensitive membrane on the inside of the human eye. 2. A scanning mechanism in optical character generation.
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