Sara Reardon
19 May 2016
As a human trial of
optogenetics for retinal diseases begins, researchers eye other applications.
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Haifeng Ye and Martin Fussenegger/ETH Zurich
Optogenetic therapies use light to control the behaviour of neurons and genes.
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Every time something
poked its foot, the mouse jumped in pain. Researchers at Circuit Therapeutics,
a start-up company in Menlo Park, California, had made the animal
hypersensitive to touch by tying off a nerve in its leg. But when they shone a
yellow light on its foot while poking it, the mouse did not react.
The treatment is one
of several nearing clinical use that draw on optogenetics — a technique in
which light is used to
control genes and neuron firing. In March, RetroSense Therapeutics
of Ann Arbor, Michigan, began the first clinical-safety trial of an optogenetic
therapy to treat the vision disorder retinitis pigmentosa.
Many scientists are
waiting to see how the trial turns out before they decide how to move forward
with their own research on a number of different applications. “I think it will
embolden people if there’s good news,” says Robert Gereau, a pain researcher at
Washington University in St Louis, Missouri. “It opens up a whole new range of
possiblilities for how to treat neurological diseases.”
Retinitis pigmentosa
destroys photoreceptors in the eye. RetroSense’s treatment seeks to compensate
for this loss by conferring light sensitivity to retinal ganglion
cells, which normally help to pass visual signals from
photoreceptors to the brain. The therapy involves injecting patients who are
blind or mostly blind with viruses carrying genes that encode light-sensitive
proteins called opsins. The cells fire when stimulated with blue light, passing
the visual information to the brain.
Chief executive Sean
Ainsworth says that the company has injected several individuals in the United
States with the treatment, and plans to enroll a total of 15 blind patients in
its trial. RetroSense will follow them for two years, but may release some preliminary
data later this year.
Rival company GenSight
Biologics in Paris is attempting to treat retinitis pigmentosa with an opsin
protein that responds to red light, which is less harsh on the eyes than blue
light. At a meeting of the Association for Research in Vision and Ophthalmology
in Seattle, Washington, earlier this month, GenSight researchers presented data
showing that injecting a gene-carrying virus into healthy monkeys made their
retinal ganglion cells responsive to light. Chief executive Bernard Gilly says
that GenSight hopes to begin a small human trial early in 2017.
Neither company
developing retinitis pigmentosa therapies expects patients to fully recover
their vision. But Gilly and Ainsworth both say that the trials will be a
success if participants gain the ability to navigate independently or even
recognize faces.
Light touch
The eye is an enticing
target for optogenetic therapies, in part because immune cells can’t enter the
eye to attack the foreign proteins introduced during such treatments. But
Circuit Therapeutics is taking a different approach with its pain therapy,
relying on light’s ability to pass through the skin.
“The nerves are
tantalizingly poised at the surface of the skin, just waiting,” says Chris
Towne, the company’s head of gene therapy. He presented preliminary data on the
treatment on 4 May at a meeting of the American Society of Gene and Cell
Therapy in Washington DC.
Unlike the retina
therapies, Circuit Therapeutics’ treatment uses opsins that prevent neurons from
firing. Shining yellow light on mice with these proteins reduces pain by
preventing pain signals from travelling to the brain. Towne hopes that the
approach, now being tested in pigs, will be the first non-retinal optogenetic
therapy to reach the clinic. He envisions a light-producing patch that humans
with severe pain sensitivity could wear on the skin and trigger when they
perform a painful activity.
Researchers still have
to determine how well opsins would function in human tissue and whether they
will be toxic, but Gereau, who is also pursuing optogenetics for pain relief,
says that the results are promising. In a paper in press at Nature Protocols,
his group showed that flashing light at similar opsins inserted into the
neurons of donated human organs can activate them or prevent them from firing.
Other applications are
not far behind. Stimulating neurons in the inner ear with light has been shown
to restore some neuron function in deaf mice. Some researchers are developing
light-emitting implants that trigger nerves to control bladder function and vocal cords.
Many others hope to use optogenetics to treat Parkinson’s disease and other
brain disorders. Such a therapy would be similar to, but more precise than,
current deep-brain-stimulation devices that trigger neuron firing.
Martin Fussenegger, a
biologist at the Swiss Federal Institute of Technology in Zurich (ETH Zurich),
says that scientists pursuing optogenetic therapies still face some technical
challenges. These include developing smaller, less
obtrusive light-emitting implants, and addressing the risk that
optogenetic treatment could overheat neurons.
Still, researchers
such as neuroscientist Ivan Soltesz of Stanford University in California are
watching industry developments closely. He hopes to use optogenetics to stop
seizures through a system that automatically flashes a light when a device
detects brain patterns that indicate a seizure is about to start or is in
progress. Such seizure-detection technologies have worked in animals3, and early trials of
similar systems that use deep brain stimulation for this purpose are promising.
Soltesz says that
optogenetics could allow more precise targeting of the right neurons, if
scientists can deliver functioning opsins into brain cells. “As soon as I see
that it's feasible I'm all over it,” he says.
Nature doi:10.1038/nature.2016.19886
http://www.nature.com/news/light-controlled-genes-and-neurons-poised-for-clinical-trials-1.19886
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