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Macular Degeneration Gene Link Raises Concerns Over RNAi-Based Therapies

NEW YORK (GenomeWeb News) – New research is providing insights into the genetics behind one form of macular degeneration — and raising red flags about the indiscriminate use of RNAi-based therapies for treating other forms of the disease.
 
An international team of researchers used gene-association studies to reveal links between an immune protein, toll-like receptor-3, and a form of age-related macular degeneration called geographic atrophy. They uncovered a protective TLR3 variant that is less active, suggesting TLR3 has a role in geographic atrophy.
 
But, researchers say, since double-stranded RNA activates the protein and could lead to retinal damage, it may be important to consider genotype before administering siRNA-based therapies for other forms of macular degeneration. The research is scheduled to appear in the Oct. 2 issue of the New England Journal of Medicine.
 
“You and me, we have a good 20 to 30 percent chance of getting macular degeneration,” co-senior author Nicholas Katsanis, an ophthalmology and genetics researcher at Johns Hopkins University’s Institute of Genetic Medicine, said in a statement. “So when the time comes for us to start thinking about intervention, we might want to get genotyped first, and then decide what kind of therapeutic paradigm might be most appropriate for us.”
 
Geographic atrophy, also known as “dry” macular degeneration, occurs when retinal pigment epithelial and photoreceptor cells in the eye break down over time, affecting an individual’s central vision. In one out of nine individuals, this eventually leads to complete vision loss. Geographic atrophy causes about ten percent of the legal blindness in the US.
 
In an effort to root out the genetic underpinnings of the disease, Katsanis, University of Kentucky retinal surgeon and ophthalmology researcher Jayakrishna Ambati, and Kang Zhang, a retinal specialist and human genetics researcher affiliated with the University of California at San Diego, led a group of researchers looking at SNPs in two genes: TLR3 and TLR4.
 
These immune system genes were selected because of inflammation’s suspected role in AMD. Past studies had also implicated several TLR4 SNPs in macular degeneration.
 
“Because of the speculation among scientists that viral infections provoke the inflammation that increases the risk of macular degeneration, we tested for associations between AMD and TLR3, which is known to support innate immunity and host defense,” Zhang said in a statement.
 
The team genotyped SNPs in TLR3 and TLR4 using an Applied Biosystems genetic analyzer and the SNaPshot Multiplex System, first testing a group of Americans of European descent at the University of Utah. They compared 359 unaffected individuals with 232 individuals with geographic atrophy, 441 with choroidal neovascularization or “wet” macular degeneration, and 152 individuals with early- to intermediate-AMD (called the soft, confluent drusen stage). 
 
Although they didn’t find any significant associations with TLR4 SNPs, the team did find a TLR3 SNP called rs3775291 that offered protection from geographic atrophy. The SNP is associated with a shift from leucine to phenylalanine at amino acid 412 of toll-like receptor 3, a protein that triggers host defenses in response to viral interlopers.
 
The researchers replicated their rs3775291 results in hundreds more Americans of European descent during two other trials.
 
Subsequent experiments suggested that rs3775291 decreased TLR3 activity. For instance, the allele decreased the cell death in primary human retinal pigment epithelial cells that were exposed to synthetic long double-stranded RNA molecules.
 
Similarly, the team found that when TLR3 was activated in wild type mouse eyes, these mice lost photoreceptors and retinal pigment epithelial cells from their eyes within about two weeks, apparently through apoptosis. The apoptosis-related cell death decreased but didn’t entirely disappear in mice lacking TLR3
 
Based on these results, the authors concluded that rs3775291’s protective effect “is probably mediated by a reduction of dsRNA-induced cell death in retinal pigment epithelial cells in vitro and in vivo.”
 
That means that there may be natural viruses that can trigger geographic atrophy. “[I]t is important to search for the existence and nature of dsRNA (viral or otherwise) in eyes affected with geographic atrophy,” the authors noted.
 
It also means that the same siRNA-based therapies designed to treat the “wet” form of AMD (choroidal neovascularization) could increase the risk of “dry” macular degeneration — and associated blindness — for those with the certain TLR3 variants.
 
In March, Ambati led a team of scientists who published work in Nature suggesting that siRNAs aimed at combating choroidal neovascularization — in which vision loss results from the growth of blood vessels behind the retina of the eye — were actually activating TLR3.
 
“If you are genetically susceptible to macular degeneration and are exposed to a virus that activates TLR3, it could lead to the death of cells in the macula,” Zhang said. “Ironically, in some individuals, using RNAi to cure wet AMD might actually increase the risk of blindness from dry AMD.”
 
As such, the researchers suggested that their findings may eventually have implications for the way macular degeneration is diagnosed and treated — and emphasized that individuals’ genotype will likely play a key role in both.
 
“These findings pave the way for using TLR3 inhibitors as a potential new therapy for dry AMD, and simultaneously highlight the importance of critically assessing the potential risk posed to patients by RNAi-based therapies, Ambati said in a statement.
 

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