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EW NEWS & OPINION 20 June 2017 can include deposits in the retina, corneal opacities, and subcapsular opacities, among others. 4 "Although tamoxifen has been associated with low frequency of retinal toxicity, it may also have protective effects on photoreceptors in the context of retinal disease," Dr. Wong said in light of this cur- rent research. "As such, the effect of tamoxifen in the retina may be worthy of further examination and study. These studies may reveal potential protective mechanisms useful in designing therapies for conditions like retinitis pigmentosa and atrophic age-related macular degeneration, which currently lack treatment." Dr. Wong's laboratory filed a patent in August 2016 to use tamoxifen in retinal degenerative disorders. EW References 1. Wang X, et al. Tamoxifen provides structural and functional rescue in murine models of photoreceptor degeneration. J Neurosci. 2017;37:3294–3310. 2. Hormone therapy for breast cancer. NIH National Cancer Institute. www.cancer.gov/ types/breast/breast-hormone-therapy-fact- sheet. Reviewed Feb. 14, 2017. 3. Nayfield SG, et al. Tamoxifen-associ- ated eye disease. A review. J Clin Oncol. 1996;14:1018–26. 4. Tsai DC, et al. Should we discontinue tamoxifen in a patient with vision-threatening ocular toxicity related to low-dose tamoxifen therapy? Eye (Lond). 2003;17: 276–8 Editors' note: Dr. Wong has no finan- cial interests related to his comments. Contact information Wong: balintfyj@nei.nih.gov by Liz Hillman EyeWorld Staff Writer inal function," Dr. Wong explained. "However, when photoreceptor cells are injured by light or disease, these microglia detect the presence of injured cells and react by attacking them. Because this immune re- sponse can speed up cell death and lead to vision loss, treatments that inhibit the immune responses may be therapeutic." Rather than directly engaging with photoreceptor cells, the inves- tigators found tamoxifen decreased these immune responses to offer a subsequent protective effect to the photoreceptor cells. How exactly tamoxifen suppresses microglia activation is still being studied, but Dr. Wong said preliminary findings show that the drug might be acting on different types of receptors. Those receptors—aside from the estrogen and estrogen-related recep- tors it's already known to affect—re- main unclear, he added. Going forward, Dr. Wong said they're studying the immune response at different doses. The dose used in the recently published mouse study was equivalent to eight times more than the U.S. Food and Drug Administration-approved dosage for breast cancer patients. Investigators are now seeing if lower doses result in protective effects for photoreceptors as well. Tamoxifen for years has been as- sociated with negative ocular effects. A review of case reports, clinical series, and clinical trials published in 1996 concluded that while "ocular toxicity is uncommon" in long-term and low-dose use of tamoxifen, "physicians should be aware of the potential for ocular toxicity." 3 Ac- cording to a more recently published letter in the journal Eye ocular side effects, many of which are revers- ible when discontinuing the drug, in Retinal Disease, National Eye In- stitute, said that tamoxifen has also been used experimentally to regulate gene expression in transgenic mice. "We had not planned to directly study tamoxifen's protective ef- fect in the eye; our discovery of its effects was serendipitous," Dr. Wong said. "We had been giving tamoxi- fen to transgenic mice to see if gene manipulation would protect against photoreceptor damage. As a control, we gave tamoxifen to non-transgen- ic mice in which gene manipulation did not occur. To our surprise, we found that tamoxifen appeared to protect non-transgenic mice." Previous work, according to this research published in The Journal of Neuroscience, found that in diseases with photoreceptor degeneration, photoreceptor loss was associated with increased levels of pro-inflam- matory cytokines and microglia cells in the retina. These microglia have been found to engage in phagocyto- sis against photoreceptor cells, while pro-inflammatory cytokines can further trigger cell death, according to the study authors. "The healthy retina contains immune cells called microglia that are thought to perform everyday maintenance to sustain normal ret- Tamoxifen researched as possible therapy for retinal diseases that currently lack treatment A drug already approved to fight breast cancer was recently found to protect photoreceptor cells in two mouse models. However, this drug has previously been associ- ated with retinal toxicity. According to a study conducted by researchers at the National Eye Institute (part of the National In- stitutes of Health [NIH]), Bethesda, Maryland, mice genetically engi- neered with a retinitis pigmentosa model or exposed light-induced photoreceptor cell degeneration were both rescued with tamoxifen, suggesting merit in further inves- tigation of this drug as a possible treatment for diseases that exhibit photoreceptor degeneration. 1 As a breast cancer drug, tamox- ifen is known to attach to cancer cells' hormone receptors, blocking estrogen, used by the tumor to grow, from attaching, according to the Na- tional Cancer Institute (also part of NIH). 2 Wai Wong, MD, PhD, chief, Unit on Neuron-Glia Interactions Drug approved to fight breast cancer shows potential in protecting photoreceptor cells " We had not planned to directly study tamoxifen's protective effect in the eye; our discovery of its effects was serendipitous. " —Wai Wong, MD, PhD ASCRS Research highlight

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