Eyeworld

EW RETINA April 2011 53 Two potential therapies developed A study published in Nature by a team of researchers from collaborative institu- tions reported on the dis- covery of a key molecular mechanism leading to the geo- graphic atrophy in dry AMD, a pri- mary cause of blindness worldwide. Led by Jayakrishna Ambati, M.D., ophthalmology department, University of Kentucky, Lexington, researchers discovered that an accu- mulation of a toxic Alu RNA mole- cule causes retinal cell death in patients with geographic atrophy. The study, "DICER1 deficit induces Alu RNA toxicity in age-related mac- ular degeneration," was published in February 2011. "We found a tremendous abun- dance of these RNA duplexes in the retinal pigment epithelium of human eyes that had geographic at- rophy," said Dr. Ambati. "We didn't find this in normal eyes or other eyes that didn't have geographic at- rophy." When the team set out to dis- cover why these RNA molecules were accumulating, they found that an enzyme called Dicer was dramati- cally reduced in eyes with geo- graphic atrophy. In properly functioning eyes, Dicer actually de- grades Alu RNA molecules. But with Dicer diminished, these toxic mole- cules can build, thereby killing reti- nal cells. Dr. Ambati and collaborators de- veloped two possible therapies that show retinal cell death could be pre- vented by either increasing Dicer or by blocking Alu RNA molecules. What researchers don't know, how- ever, is why Dicer malfunctions in the first place. "One hint we have is that when we take retina cells and expose them to oxidative stress, the levels of Dicer go down tremendously," said Dr. Ambati. "Oxidative stress has been postulated as one of the incit- ing events or contributory causes to macular degeneration. We don't know if that's the case for sure, but it's something to look at more care- fully." Dr. Ambati hopes clinical trials will begin toward the end of this year, noting there are still mysteries left to puzzle out. For example, find- ing out why Dicer decreases is criti- cal. Also, discovering where these Alu RNA molecules are coming from in the genome would provide under- standing of why this process hap- pens and how scientists could thera- peutically target it. "The challenges from a medical perspective are to develop drugs that are suitable for human administra- tion and that last a long time," he said. "Another challenge is the drug delivery strategy. Geographic atro- by Faith A. Hayden EyeWorld Staff Writer Breakthrough research in AMD released continued on page 54

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