Reducing photoreceptor death in dry AMD using anti-purinergic agents
We will first examine how photoreceptors die in an animal model of age-related macular degeneration, and specifically look for evidence that a molecule called ATP is released from dying photoreceptors. Secondly, we will treat animals with novel compounds that block the actions of ATP and see whether this slows disease progression.
This is an important study because drugs that block the actions of ATP are already under intense investigation for possible use in treating pain. At the conclusion of this project, the mechanisms that are involved in photoreceptor death during age-related macular degeneration will be better understood. In addition, specific information about the value of using drugs that block the action of ATP will be known.
The team’s results showed that purines play a very important role in contributing to photoreceptor death in some types of animals engineered to have retinal degenerative disease. They found that the receptor to which ATP binds, called P2X7, was increased in a model of photoreceptor death, suggesting that ATP could contribute to the death of these cells. In addition, photoreceptors from mice that lack the P2X7 receptor showed a slower rate of death than photoreceptors that express this receptor. A drug known to block the action of P2X7 receptors also slowed the death of photoreceptors. These are exciting data that implicate ATP in photoreceptor death and provide a potential therapeutic target in treating blinding conditions.
With respect to AMD, the team was not able to firmly establish whether ATP contributes to photoreceptor death in this disease. In animals that lack a protein implicated in AMD (called the CX3CR1-null mouse), there was no change in expression of key molecules involved in the regulation of purines (such as the P2X7 receptor). Rather, they found that these mice lose cones gradually via a mechanism involving altered transport of proteins across the photoreceptor. More work will be necessary to further understand the mechanism of photoreceptor death in these mice, and also to further evaluate the role that purines play in photoreceptor death in AMD.
First published on: April 1, 2010
Last modified on: March 18, 2013