Protein Might One Day Prevent Blindness
THURSDAY, Jan. 8 -- Researchers working with mice have identified a protein that appears to prolong the lives of retinal cells in both healthy and diseased eyes.
The discovery could one day lead to treatments that would prevent blindness among people genetically predisposed to develop retinal disease, the scientists said.
The protein, known as histone deacetylase 4 (HDAC4), is naturally produced by both mice and humans and is typically involved in the regulation of bone and muscle development.
Reducing the amount of HDAC4 to below-normal levels appears to lead to premature photoreceptor cell death in healthy eyes, the study revealed. In contrast, increasing quantities of this protein to above-normal levels appears to protect the lifespan of these critical vision cells -- both in healthy mouse eyes and in those mice suffering from a genetic flaw, also present in humans, that gives rise to degenerative retinal disease.
The finding -- if replicated in people -- could ultimately lead to new interventions to prevent such disease-driven blindness, or even to the development of methods to restore lost sight to diseased retinas.
"There are some inherited genetic defects that lead to the death of the two types of photoreceptor cells in the eye that capture light, first directly killing the rod cells and then the cone cells which depend on rod cell survival," explained study author Bo Chen, a postdoctoral research fellow with the Howard Hughes Medical Institute at Harvard Medical School in Boston. "So, this mutation eventually leads to complete blindness."
"But what we found," Chen noted, "is that we could actually promote the survival of these genetically affected photoreceptors by introducing more of this particular protein, even though the photoreceptors themselves continue to remain genetically defective."
Chen and his colleagues report their findings in the Jan. 9 issue of Science.
The findings are based solely on a series of neural cell experiments, focused on the retinal health of live mice, that were designed to assess the impact of both under-expression and overexpression of the HDAC4 protein.
Subsequent lab work led the researchers to determine that in sufficient quantities the protein indeed displays a protective effect against eye cell death and thereby has an "essential role in neuronal survival," they wrote.
Yet despite expressing enthusiasm for his current work, Chen emphasized the ongoing nature of the effort.
"Even though the genetics are the same in mice and humans, at this stage it's really very experimental," he stressed. "And much more work needs to be done before we know this will be efficacious in humans."
Nevertheless, Dr. Robert Cykiert, a clinical associate professor of ophthalmology at New York University Langone Medical Center in New York City, described the current work as an "impressive" effort.
"Clearly a lot of people go blind from retinal diseases," he said, noting that glaucoma and macular degeneration are two serious conditions that result from retinal cell death. "And this protein they worked with appears to be what we call neuro-protective, in that it has protective benefits on both the photoreceptor layer that gets damaged in macular degeneration as well as on the ganglion cell layer which is damaged by glaucoma. So this finding could actually turn out to be a major accomplishment, affecting a lot of patients down the road."
However, Rando Allikmets, an associate professor of ophthalmology, pathology and cell biology at Columbia University in New York City, took Chen's cue in cautioning that the true measure of the current work awaits human clinical trials.
"It's a very good study, an interesting observation and a very encouraging finding that will definitely lead to an investigation of this pathway for possible therapeutic targets," he said. "But the problem is that they have identified a protein involved with very basic functions -- including muscle development and bone growth -- so it's very difficult to predict if what they did in mice can be done in humans at all and, even if it can, if it will work in the same way."
"Of course, it's a mouse study," he acknowledged. "So you certainly don't know if what they've found will be reproduced in patients. And in any case, it would take 10 years to develop any drugs from this that might benefit people. So, yes, it's just a first step."
For more on the causes of blindness, visit the World Health Organization.
Posted: January 2009