After doing DNA analysis of the samples, the group identified a genetic variant that promotes low tlr3 activation. Patients possessing this variant were in a sense genetically “protected” against dry macular degeneration, whereas patients with a variant that promotes high tlr3 activity were 20 percent more likely to develop dry macular degeneration.
Since tlr3 is activated in response to RNA, Zhang says that this genetic association may raise concerns over RNA-based therapies for wet macular degeneration. Currently, clinical trials are under way for RNAi therapies to treat wet macular degeneration and turn off the genes responsible for blood-vessel overgrowth in the eye. However, Zhang says that these RNA-based therapies may have adverse effects for people with the genetic variant that increases tlr3 activity. In essence, the otherwise therapeutic RNA would trigger tlr3 to kill cells in the retina, which could ultimately lead to vision loss.
“We are able to see if we can develop a therapy to modulate or inhibit tlr3 to treat dry macular degeneration,” says Zhang. “Also, people undergoing RNAi therapy need to be aware of potential harmful effects of tlr3 activation.”
However, Rando Allikmets, director of the molecular-genetics laboratory at Columbia University, says that, compared with other genes associated with macular degeneration, the tlr3-linked association that Zhang found is not very strong, and should not have much effect on RNAi therapies. “Their data shows that [tlr3] is technically associated with dry macular degeneration,” says Allikmets. “But even if there is something, 20 percent risk [of dry macular degeneration] is very, very minor.”
More likely, Katsanis says, the group’s findings may illustrate a masking effect for otherwise beneficial RNAi therapy. For example, patients who unknowingly overexpress tlr3, and who are treated with RNAi therapy, may still experience the positive effects of RNA, but also the negative effects of cell death. The overall effect may be no effect at all.
“The genotype may counterbalance beneficial effects of RNAi treatment, and the final analysis may be that this treatment is noneffective, and you may be throwing away a perfectly good treatment,” says Katsanis. “What this says is, potentially, people with the right variant might be better candidates for RNAi therapies, and vice versa, and we may target disease more effectively according to genotype.”