New Understanding in Cause of GA type of AMD

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There is new understanding in the cause of geographic atrophy (GA) type of age-related macular degeneration, a major cause of untreatable blindness, which could provide new pathways to therapy.

Dr. Jayakrishna Ambati, University of Kentucky, and his team have published their discovery of a molecular mechanism in GA in the February 6 online issue of Nature.

Geographic atrophy (GA) occurs in the later stages of the of age-related macular degeneration (AMD). AMD is a disease that causes progressive damage to the macula, the center part of the retina which allows us to see fine detail, from retinal pigmented epithelium (RPE) cell degeneration. This loss of vision in the center of the visual field interferes with reading, driving, recognizing faces or color and usually for fine, detailed work.

AMD is the main cause of blindness in elderly people in Western countries, occurring in approximately 30% of individuals over seventy years of age.

Geographic atrophy (GA) involves a breakdown or wasting away of the photoreceptors. There are currently no approved GA therapies for the nearly one million individuals affected in the United States.

Ambati and colleagues noticed the enzyme DICER1 was less active in the retina of people with the more common "dry form" of AMD. This reduced DICER1 activity allows an accumulation of a toxic type of RNA, called Alu RNA, causing retinal cells to die in patients with GA. In a healthy eye, DICER1 is necessary for destroying the Alu RNA particles.

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In the lab, the researchers were able show that conditional ablation of DICER1, but not seven other miRNA-processing enzymes, induces RPE degeneration in mice.

When the researchers turned off the gene which makes the enzyme DICER1 in human RPE cells, there was an accumulation of Alu RNA. The same occurred in mice by turning off the gen which makes the Alu-like B1 and B2 RNAs in mouse RPE.

Alu RNA is increased in the RPE of humans with GA, and this pathogenic RNA induces human RPE cytotoxicity and RPE degeneration in mice.

Antisense oligonucleotides targeting Alu/B1/B2 RNAs prevent DICER1 depletion-induced RPE degeneration despite global miRNA downregulation.

DICER1 degrades Alu RNA, and this digested Alu RNA cannot induce RPE degeneration in mice.

Ambati’ team developed two potential therapies - the first one involves increasing Dicer levels in the retina by "over-expressing" the enzyme and the second one involves blocking Alu RNA using an "anti-sense" drug that binds and degrades this toxic substance.

It must be remembered that this work has to be validated by other researchers, but if it is then it offers the potential of new pathways to therapy.

Source
DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration; Nature (2011), doi:10.1038/nature09830

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