When the eyes of her mice looked normal, Xu Wang was certain she had done something wrong. She was blasting the mice with blinding light to study how a specific gene affected the animals’ response to eye injury. All the mice were given the drug tamoxifen. Half were engineered to respond to the drug by disabling the gene — a step that would protect their eyes. The control mice, with all genes intact, should have lost sight as photo-receptors — the light-sensitive cells in the retina — died.
Instead, the retinas of the control mice looked just fine. “I was kind of despondent because it didn’t agree with our hypothesis,” Wang says. She and her mentor, Wai Wong, both ophthalmologists at the National Eye Institute in Bethesda, Md., could have started over with another kind of mouse. But they decided to do the test again. And again.
The spared vision was no mistake. Many experiments later, Wang, Wong and colleagues have shown that tamoxifen, a drug used to treat breast cancer, can help preserve photoreceptors — and sight — in mice with eye injuries.
After exposure to blinding light, injured photoreceptors send distress signals to summon microglia, immune cells that are the first line of defense in the brain and spinal cord. Microglia support photoreceptors by keeping the connections between them intact. But a photoreceptor “SOS” brings microglia swarming in to destroy damaged photoreceptors, resulting in vision loss. The same happens in progressive genetic vision disorders such as retinitis pigmentosa. The microglia’s murderous tendencies are meant to protect, but, Wong notes, their enthusiastic efforts can be overkill.
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The better to see you with
Exposure to blinding light killed photoreceptor cells in the retinas of mice (left, dying cells colored pink). Animals given tamoxifen before the light (right), had almost no cell death.
When mice ate chow containing tamoxifen (about six to eight times the dose usually given to humans), the microglia didn’t overreact and the photoreceptors were spared, the researchers found. Tamoxifen offered the same protection in mice with a form of retinitis pigmentosa. “The killing power of microglia can be reduced by tamoxifen and this resulted in protection,” Wong says. The group reported its findings in the March 22 Journal of Neuroscience.
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The researchers are looking into whether lower doses of the drug can be protective, too. And there are plenty of other questions, such as how exactly tamoxifen protects against microglial malfeasance. Other scientists have shown that tamoxifen and similar drugs might also reduce nerve cell damage in the spinal cord and brain. The drug is widely used to treat women with certain types of breast cancer. But the eyes present their own challenges. In rare cases, tamoxifen has been tied to vision loss in women taking the drug. The scientists didn’t see any sign of that in their mice, but Wong is quick to note that mice are not people.
Wang recalls her early days with patients facing blindness. “I felt so helpless,” she says. “I thought, ‘I want to find a way to solve their problems.’” She has new optimism. “It opens a new window,” she says. “An old drug can be used in a new way.”