MyVisionTest News Archive
Sep 18, 2008
Macular Degeneration Gene Link Raises Concerns Over RNAi-Based Therapies
New research is providing insights into the genetics behind dry macular degeneration — and raising red flags about the indiscriminate use of RNAi-based therapies for treating the wet form of the disease.
An international team of researchers used gene-association studies to reveal links between an immune protein, toll-like receptor-3 (TLR3), and a form of dry age-related macular degeneration (AMD) called geographic atrophy. They uncovered a protective TLR3 variant that is less active in people without the disease, suggesting activation of TLR3 may play a role in the development of geographic atrophy.
But, researchers say, since double-stranded RNA activates TLR3 and, therefore, could lead to geographic atrophy, it may be important to consider genotype before administering siRNA-based therapies for wet AMD. 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 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 occurs when retinal pigment epithelial and photoreceptor cells in the eye break down over time, affecting an individual’s central vision. Geographic atrophy causes about ten percent of the legal blindness in the US.
The research team 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).
They found a varient of TLR3 called rs3775291 that offered protection from geographic atrophy. Subsequent experiments suggested that rs3775291 decreased TLR3 activity.
Similarly, the team found that when TLR3 was activated in mouse eyes, these mice lost photoreceptors and retinal pigment epithelial cells 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 could increase the risk of “dry” macular degeneration 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 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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GenomeWeb News
Tags: dry AMD, genetics, RNA interference
New research is providing insights into the genetics behind dry macular degeneration — and raising red flags about the indiscriminate use of RNAi-based therapies for treating the wet form of the disease.An international team of researchers used gene-association studies to reveal links between an immune protein, toll-like receptor-3 (TLR3), and a form of dry age-related macular degeneration (AMD) called geographic atrophy. They uncovered a protective TLR3 variant that is less active in people without the disease, suggesting activation of TLR3 may play a role in the development of geographic atrophy.
“You and me, we have a good 20 to 30 percent chance of getting macular degeneration,” co-senior author Nicholas Katsanis 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 occurs when retinal pigment epithelial and photoreceptor cells in the eye break down over time, affecting an individual’s central vision. Geographic atrophy causes about ten percent of the legal blindness in the US.
The research team 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).
They found a varient of TLR3 called rs3775291 that offered protection from geographic atrophy. Subsequent experiments suggested that rs3775291 decreased TLR3 activity.
Similarly, the team found that when TLR3 was activated in mouse eyes, these mice lost photoreceptors and retinal pigment epithelial cells 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 could increase the risk of “dry” macular degeneration 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 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.
Read more...
GenomeWeb News
