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retinal diseases

Snapshots of Life: Lighting up the Promise of Retinal Gene Therapy

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mouse retina

Caption: Large-scale mosaic confocal micrograph showing expression of a marker gene (yellow) transferred by gene therapy techniques into the ganglion cells (blue) of a mouse retina.
Credit: Keunyoung Kim, Wonkyu Ju, and Mark Ellisman, National Center for Microscopy and Imaging Research, University of California, San Diego

The retina, like this one from a mouse that is flattened out and captured in a beautiful image, is a thin tissue that lines the back of the eye. Although only about the size of a postage stamp, the retina contains more than 100 distinct cell types that are organized into multiple information-processing layers. These layers work together to absorb light and translate it into electrical signals that stream via the optic nerve to the brain.

In people with inherited disorders in which the retina degenerates, an altered gene somewhere within this nexus of cells progressively robs them of their sight. This has led to a number of human clinical trials—with some encouraging progress being reported for at least one condition, Leber congenital amaurosis—that are transferring a normal version of the affected gene into retinal cells in hopes of restoring lost vision.

To better understand and improve this potential therapeutic strategy, researchers are gauging the efficiency of gene transfer into the retina via an imaging technique called large-scale mosaic confocal microscopy, which computationally assembles many small, high-resolution images in a way similar to Google Earth. In the example you see above, NIH-supported researchers Wonkyu Ju, Mark Ellisman, and their colleagues at the University of California, San Diego, engineered adeno-associated virus serotype 2 (AAV2) to deliver a dummy gene tagged with a fluorescent marker (yellow) into the ganglion cells (blue) of a mouse retina. Two months after AAV-mediated gene delivery, yellow had overlaid most of the blue, indicating the dummy gene had been selectively transferred into retinal ganglion cells at a high rate of efficiency [1].


Creative Minds: Reverse Engineering Vision

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Networks of neurons in the mouse retina

Caption: Networks of neurons in the mouse retina. Green cells form a special electrically coupled network; red cells express a distinctive fluorescent marker to distinguish them from other cells; blue cells are tagged with an antibody against an enzyme that makes nitric oxide, important in retinal signaling. Such images help to identify retinal cell types, their signaling molecules, and their patterns of connectivity.
Credit: Jason Jacoby and Gregory Schwartz, Northwestern University

For Gregory Schwartz, working in total darkness has its benefits. Only in the pitch black can Schwartz isolate resting neurons from the eye’s retina and stimulate them with their natural input—light—to get them to fire electrical signals. Such signals not only provide a readout of the intrinsic properties of each neuron, but information that enables the vision researcher to deduce how it functions and forges connections with other neurons.

The retina is the light-sensitive neural tissue that lines the back of the eye. Although only about the size of a postage stamp, each of our retinas contains an estimated 130 million cells and more than 100 distinct cell types. These cells are organized into multiple information-processing layers that work together to absorb light and translate it into electrical signals that stream via the optic nerve to the appropriate visual center in the brain. Like other parts of the eye, the retina can break down, and retinal diseases, including age-related macular degeneration, retinitis pigmentosa, and diabetic retinopathy, continue to be leading causes of vision loss and blindness worldwide.

In his lab at Northwestern University’s Feinberg School of Medicine, Chicago, Schwartz performs basic research that is part of a much larger effort among vision researchers to assemble a parts list that accounts for all of the cell types needed to make a retina. Once Schwartz and others get closer to wrapping up this list, the next step will be to work out the details of the internal wiring of the retina to understand better how it generates visual signals. It’s the kind of information that holds the key for detecting retinal diseases earlier and more precisely, fixing miswired circuits that affect vision, and perhaps even one day creating an improved prosthetic retina.