Ways of reducing vision loss in an animal model of Age-Related Macular Degeneration

Erica Fletcher, OD, PhD
The University of Melbourne (Melbourne, Australia)
Year Awarded:
2010
Grant Duration:
April 1, 2010 to March 31, 2012
Disease:
Macular Degeneration
Award Amount:
$99,196
Grant Reference ID:
M2010020
Award Type:
Standard
Award Region:
International
Erica Fletcher, OD, PhD

Reducing photoreceptor death in dry AMD using anti-purinergic agents

Summary

We think that a molecule called ATP is released from dying photoreceptors early in the course of age-related macular degeneration that causes and accelerates the death of neighboring cells. In addition, we predict that drugs that block the actions of ATP will slow photoreceptor death and ultimately preserve vision. This project will examine this question in an animal model of age-related macular degeneration.

Details

Vision loss in some forms of age related macular degeneration is associated with the death of cells called photoreceptors. This project will determine whether substances released from dying photoreceptors cause the death of neighboring photoreceptors causing acceleration of vision loss. In addition we will examine whether treatments that block the actions of these released substances (called ATP) slow the death of photoreceptors and preserve vision. This project addresses a novel mechanism of photorecepetor death, and considers whether a relatively unexplored class of drug can be used in the treatment of retina disease.

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.

Research Updates

The aim of this project was to examine the benefit of using a new type of drug, called an anti-purinergic, in slowing the death of light-detecting cells (photoreceptors) in animal models of dry age-related macular degeneration (dry AMD). Dr. Fletcher’s team proposed that when photoreceptors die, the purine, called ATP, is released and affects neighboring photoreceptors. Blocking the actions of ATP should slow the death of photoreceptors, and therefore could be a potential treatment for dry AMD.

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.

Publications

Vessey KA, Fletcher EL (2012) Rod and cone pathway signaling is altered in the P2X7 receptor knockout mouse. PLoS One 7:e29990 PubMed Icon Google Scholar Icon

Fletcher EL, Jobling AI, Vessey KA, Luu C, Guymer RH, Baird PN.(2011) Animal models of retinal disease. Prog Mol Biol Transl Sci 100:211-86 PubMed Icon Google Scholar Icon

Vessey KA, Jobling AI, Greferath U, Fletcher EL (2012) The role of the P2X7 receptor in the retina: cell signaling and dysfunction. Adv Exp Med Biol 723:813-9 PubMed Icon Google Scholar Icon

Don't miss out.
Receive research updates, inspiring stories, and expert advice
Please enter your first name.
Please enter your last name.
Keep me informed about: *
Please select at least one.
You must select at least one disease category.