Gene therapy restores sight to blind mice

A gene therapy technique that can help to repair the retina and restore lost vision has been tested successfully on mice by scientists at the University of Oxford.
05 October 2017


Gene therapy in the mammalian retina for retinitis pigmentosa


A gene therapy technique that can help to repair the retina and restore lost vision has been tested successfully on mice by scientists at the University of Oxford.

The retina is the light-sensitive sheet of tissue at the back of the eye where rod and cone cells convert light waves into electrical signals that the brain can understand. But in diseases like retinitis pigmentosa, these cells die off, leaving patients unable to see.

Now Samantha De Silva and her colleagues have developed a way to use a harmless virus to deliver genetic instructions that can make other surviving healthy cells in the retina become light sensitive and take over the role of the missing rods and cones.

Publishing in the journal PNAS, De Silva and her colleagues engineered a harmless adeno-associated virus (AAV), to equip it with a copy of the human melanopsin gene, known as OPN4. This codes for a light-sensitive molecule that is used by one population of cells in the retina to detect light at the blue end of the spectrum.

Purified samples of the modified virus were injected beneath the retina in a group of mice with a rodent form of blindess resembling retinitis pigmentosa.

Alongside a control group of uninjected animals, the mice were tested at 4 and 15 months after the treatment to assess their vision and to see whether their pupils responded to light, whether the retina generated the correct pattern of electrical signals when light fell upon it, and if the animals could recognise objects, indicating that retinal signals were being relayed correctly to their brains.

The electrical tests showed that over 40% of retinal cells examined fired off impulses when light shone on them compared with only 18% in the control, untreated mice. Pulses of light shone into the eyes also provoked blood flow changes in the visual areas of the animals' brains, which the researchers suggest reflects neurological processing of the signals arriving from the eye. Pupil constriction in response to light was also present, and the treated mice spent far less time in brightly-lit areas compared with the control animals. The virus-injected mice also showed improved ability to recognise objects in their surroundings, suggesting that they were able to make sense of the visual information being presented to their nervous systems.

Examination of the retinae from the mice shows that the viral injections had accessed a range of cells in the retina that are not normally involved in detecting light directly. Adding the melanopsin gene to these cells, De Silva found, had made them light-sensitive so that they could partly take over the function of the missing rods and cones.

"This is encouraging," De Silva says, "because melanopsin is normally naturally present in the human retina, so it's less likely to trigger an immune response when we add more of it with our gene therapy." The retina, she points out, is also an immune-privileged site meaning that the immune system is normally excluded, reducing the risk of reactions against the viral injections.

One downside of the approach is that melanopsin is not a "rapid responder" like the related rhodopsin molecule found in rods and cones. This means that, when illuminated, it does not turn on and off with the same speed, meaning that it's much less helpful for dynamic vision or interpreting movement. "It's much more suited for seeing static objects, like the location of a door, or a window, or something in the road. But, if you previously could see nothing, that's a big step forward," explains De Silva. 

So is a human clinical trial on the cards? "That's about 3 years away," she says. "Fortunately, there are other retinal gene-therapy clinical trials already on-going in Oxford for several other eye conditions, so we can build on those to speed up the route to the clinic for this new approach."


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