Everything is Illuminated: Restoration of vision after transplantation of photoreceptors

ResearchBlogging.orgThe retina is a paper-thin layer of tissue found at the back of the eye that allows us to see light.  Without a retina (or the cells that make it up), we’re blind.  Because mutations that cause the retina to break-down affect nearly 1 in 4,000 people world-wide, researchers eagerly study new ways to treat this condition.  So far, they have identified over 50 genes that, when mutated, cause retinal degeneration and blindness.  In fact, some of the earliest successes in gene therapy involved cases of retinal degeneration and blindness. Now researchers are trying something new: retinal transplants, or physically moving cells from healthy eyes to those that are unhealthy.  In a recent study published by Pearson et al. (2012) in Nature (not open-access, sorry), researchers moved rod photoreceptor cells from healthy mice to those that suffered from night-blindness and — boom! — restored vision to the mice. They even have a cool video.

Photoreceptors are retinal cells responsible for detecting light under dark conditions, like when you get up in the middle of the night to go to the bathroom or find a snack to eat.  Mutant mice that lack the genes necessary for rod-function have no night (scotopic) vision, though they do have regular color (photopic vision).  In this study, Pearson et al. made the rod precursor cells of healthy mice glow green using  GFP so that the cells would be easy to identify (see the figure below). They then injected these cells into the retinas of mice that lack a gene, Gnat1, necessary for the rods to function.  Finally, they used a series of tests to answer the question, “Do the transplanted rod cells work and allow the blind mice to see?”

To determine whether or not the transplanted rod precursor cells actually developed into mature, functioning rods, the researchers tried several things.  First, they measured the expression of multiple genes that are usually expressed in normal rods (e.g., alpha-transducin, rhodopsin, recoverin, and phosducini).  In all cases, the transplanted cells correctly generated and expressed these genes.  Then they checked whether or not the transplanted rods actually look like normal rods.  They stained and imaged the rods and found that the transplanted rods had the appropriate outer-segments and formed connections with other cells in the expected triad shape.  Together, these observations suggested that the transplanted rod precursor cells do develop into normal, healthy rods in treated mice (see figure below).

Structure and expression of transplanted rod cells expressed a rod-specific gene (NRL) and GFP.

But looking and acting normal isn’t enough.  The researchers also wanted to know if the transplanted rod cells work correctly — can they help the blind mice see?  To determine whether or not this was the case, the researchers then performed several tests of rod function and visual acuity.  The researchers recorded electrical pulses from the rod cells and found that these pulses were present, though they were not as strong compared to healthy mice.  The researchers attributed this result to technical difficulties in recording the pulses. Next the researchers used electroretinography (ERG) to measure electrical signals from the whole eye.  But the researchers found that these signals were weak as well.  Together, these two results suggested that transplanted rod cells may look good, but function poorly.

But assuming that even weak signals might still be useful, the researchers gave up measuring the eye and went straight to the brain and the body.  They measured the visual cortex of mice with and without transplanted rod cells.  As expected, the visual cortex of wild-type mice showed lots of activity, but not those of untreated blind mice, or of blind mice treated with a sham-injection.  This result suggested that a weak but functional signal was making its way from the transplanted rod cells to the brain.  The researchers then perform two behavioral tests to see if the signals in the brain are translated into behaviors that we would associate with sight.  The researchers tested the optokinetic reflex of treated and untreated eyes from the same mouse.  The optokinetic reflex is a behavior in which our eyes automatically follow the trail of a moving object (see the GIF at the wikipedia link).  The treated eyes showed a strong optokinetic response that suggested that they could detect the object, though the benefit was still small.  Finally, the researchers put the mice through a Y-shaped water maze, created the cool video below.  The researchers tested wild-type mice (minute 1:00), two sets of blind controls (minutes 1:45 and 3:15), and the mice with transplanted rods (minute 4:45).  The mice with transplanted rods performed better than the two blind controls and almost as well as the wild-type mice.  Tissue transplant, vision restored!  Look for it in a clinic near you — in another 5 to 10 years.

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