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Tamoxifen dampens immune response, protecting retina from damage

The breast cancer drug tamoxifen appears to protect light-sensitive cells in the eye from degeneration, according to a new study in mice. The drug prevented immune cells from removing injured photoreceptors, the light-sensitive cells of the retina in the back of the eye.

The study, recently reported in the Journal of Neuroscience, suggests tamoxifen might work for the treatment of age-related macular degeneration (AMD) and retinitis pigmentosa (RP), blinding diseases that lack good treatment options.

The study was conducted by researchers at the National Eye Institute (NEI), part of the National Institutes of Health.

Although commonly used for cancer treatment, tamoxifen is used in the laboratory as a tool to activate specific genes in genetically engineered mice.

The tool allows researchers to turn genes on and off in specific tissues at will.

Wai Wong, M.D., Ph.D., chief of NEI's Unit on Neuron-Glia Interactions in Retinal Disease, and his team were using tamoxifen for this purpose when they noticed something odd.

Xu Wang, Ph.D., staff scientist in the Wong laboratory and lead author of the study, observed that mice treated with tamoxifen gained resistance to light-induced eye injuries.

Light injury, induced by exposing mice to short-duration, high-intensity light, normally leads to degeneration of photoreceptors.

But in the tamoxifen-treated mice, the team unexpectedly observed little to no photoreceptor degeneration.

The team investigated the effects of tamoxifen on light-induced photoreceptor degeneration in normal mice and mice with a disease similar to RP.

Live retinal imaging and tissue analyses showed significantly lower levels of photoreceptor degeneration, compared to control mice that did not received tamoxifen.

Tamoxifen-treated mice also demonstrated higher photoreceptor function, compared to controls.

How was tamoxifen exerting this protective effect?

In an earlier study in 2015, Wong showed that light injury triggers a neurotoxic immune response in the retina.

"The immune system becomes alerted to the stressed photoreceptors and goes into culling mode, clearing them out of the retina,” he explained.

Wong and his team surmised that tamoxifen was inhibiting this immune response, rather than protecting the photoreceptors directly.

To investigate this hypothesis, Wong’s team cultured microglia -- immune cells in the retina -- and found that tamoxifen reduced their ability to remove and kill photoreceptor cells.

Tamoxifen also reduced levels of inflammatory cytokines -- signalling molecules that trigger inflammation -- produced by the microglia.

Tamoxifen did not appear to directly influence the physiology of photoreceptors or protect photoreceptors in the absence of microglia, suggesting that the inhibition of microglia is a key mechanism underlying tamoxifen’s protective effect.

The investigators are currently studying at molecular level how tamoxifen is able to inhibit the microglia.

In August 2016, Wong’s laboratory filed a patent for use of tamoxifen in retinal degenerative disorders.

The new use of the drug is unexpected, as tamoxifen’s only previously known association with the retina had been a low risk of retinopathy among breast cancer patients.

RP is a group of rare genetic disorders affecting the retina.

Worldwide, RP affects about 1 in 4,000 people.

Symptoms typically appear during childhood and slowly progress over many years, often causing blindness.

AMD is a leading cause of vision loss among people age 50 and older.

About two million Americans have AMD, which affects central vision.

The tamoxifen dose used in Wong’s mouse study was equivalent to eight times the FDA-approved dose for breast cancer.

The researchers are currently investigating whether the protective effects are retained at lower doses.

The work "sets us up for a clinical trial in the not-so-distant future," said Wong. “Translation to the clinic can happen reasonably rapidly because tamoxifen, as an FDA-approved drug, already has a well-characterised safety profile,” he explained.

Source: National Eye Institute

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