Scientists have developed “a new treatment for the most common form of blindness”, The Daily Telegraph has reported. The newspaper said researchers have found that the lack of a protective protein, called DICER1, is behind one form of age-related macular degeneration (AMD).
The findings come from a study which looked at “geographic atrophy”, an advanced stage of the common condition known as dry AMD.
In dry AMD, light-sensitive cells in an area at the back of the eye (the retina) begin to break down. The researchers examined donor eyes with the condition, human retina cells in the laboratory and the eyes of genetically engineered mice. They found that a lack of DICER1 in retina cells caused a toxic molecule (called Alu RNA) to build up, which led to the death of retina cells.
This extensive research has provided an insight into the potential causes of the death of retina cells in one form of AMD. It is not yet clear whether the laboratory methods used in this study could also be used as a treatment in humans, as some newspapers have suggested. Further rigorous animal and human studies are probably needed before we can tell if these or similar methods can be used to treat this form of AMD.
The study was carried out by researchers from the University of Kentucky and other research centres in the USA, Korea, Australia and Canada. The researchers were funded by several charitable and governmental bodies. The study was published in the peer-reviewed scientific journal Nature.
The study was reported by BBC News, the Daily Express and The Daily Telegraph. BBC News covered this story in a balanced way, its headline indicating that this research has found a clue to understanding the causes of this type of AMD rather than developing a therapy. The headlines in the Telegraph and Express highlighted the possibility of new treatments, and the Telegraph ’s report stated that one of the researchers has “created two treatments that could potentially halt the march of the disease”. The newspaper said that these are being patented and could begin to be tested in humans by the end of this year. The study itself does not state whether the methods used are being considered for testing in humans.
This animal and laboratory study looked at whether a protein called DICER1 might play a role in the dry form of age-related macular degeneration (AMD). AMD is usually split into two forms, called dry and wet AMD. Dry AMD is much more common, and begins with the formation of yellow deposits (drusen) at the central part of the retina, known as the macula. This leads to a blurred image around the central area of vision. The condition gradually advances, leading to the breakdown of the light-sensitive pigmented cells of the macula. It is not known what causes these cells to die. The researchers were interested in this advanced stage of dry AMD, which is sometimes called geographic atrophy.
The other, less common form of AMD is wet AMD, which was not investigated in this study. Wet AMD is a progression of dry AMD, where new, abnormal blood vessels start to grow within the damaged retina.
The researchers carried out various experiments, largely in mice, to look at the DICER1 protein and the DICER1 gene which makes the protein. They wanted to see what would happen if these were not present.
The researchers first looked at 10 human eyes with geographic atrophy (GA) and 11 human eyes without the condition to see how much DICER1 protein was present in the retinal pigmented epithelium (RPE), a layer of pigment-filled cells lining the inside of the eye. They also looked at the level of DICER1 protein in human eyes with other conditions, and eyes from mouse models of other retinal degeneration diseases.
Next, they genetically engineered mice that lacked the DICER1 protein in their retinas, and examined the effect on their retinas. They also looked at what happened to human RPE cells grown in the laboratory when they were treated to “switch off” the DICER1 gene.
The researchers also carried out a large number of further experiments, which looked at the effects of switching off the DICER1 gene in the human and mouse cells, and how these changes caused them to die. The DICER1 protein normally breaks down a certain type of nucleic acid molecule called double-stranded RNA. The researchers, therefore, looked at whether the build-up of different types of double-stranded RNA molecules might cause the cell death. They initially looked at the possibility that the build-up of small molecules called microRNAs might be responsible, but their experiments suggested that this was not the case. They then looked at which other double-stranded RNA molecules were building up in the RPE cells of eyes with GA.
The researchers found that eyes with geographic atrophy (GA) contained less DICER1 protein in the pigmented cells of their retinas than normal eyes. The amount of DICER1 protein was not reduced in the pigmented retinal cells in human eyes with other conditions, such as retinal detachment, or in the eyes of mouse models of other retinal degeneration diseases.
They found that if they genetically engineered mice to lack the DICER1 protein in their retinas, the retinal pigmented epithelium (RPE) cells started to die. If the DICER1 gene was switched off in human RPE cells in the laboratory, they also stated to die.
Further experiments showed that nucleic acid molecules called Alu RNAs built up in the RPE cells of eyes with GA but not in the RPE cells of normal eyes. The researchers went on to show that although switching off the DICER1 gene in human RPE cells in the laboratory usually causes them to die, blocking the formation of Alu RNAs at the same time stopped the cells from dying. They found similar results in mice.
The researchers concluded that DICER1 plays a role in keeping retinal pigmented epithelial cells alive, and that it does so by preventing the build-up of toxic Alu RNA. They say they have shown that the accumulation of Alu RNA can directly cause disease-related changes in human cells and that their research has identified “new targets for a major cause of blindness”.
This extensive research has provided an insight into the potential causes of retinal pigment cell death in advanced stages of dry AMD. As the authors note, what triggers the initial reduction of DICER1 in people with the condition is unknown, and further studies will need to investigate this.
These findings suggest that drugs to boost DICER1 or reduce Alu RNA might potentially reduce retinal cell death (geographic atrophy) seen in advanced dry AMD. It is not yet clear whether the same methods used to prevent the build-up of Alu in cells in this laboratory study would be appropriate for use in humans. There will probably be much more research aimed at identifying whether these methods could be used, or identifying other ways to achieve the same results. Once such drugs or methods have been identified, they will need to undergo the usual rigorous testing process in animals and humans before they could be more widely used.