New Approach Reverses Amblyopia in Animals | MIT News


Amblyopia is the most common cause of vision loss in children, according to the US National Eye Institute. It occurs when the visual experience is disturbed during early childhood, for example by a cataract in one eye. Even after the cataract has been removed, vision through the affected eye is impaired due to the inability of that eye to develop strong connections in the brain. The current treatment of covering the “good” eye with a patch to strengthen the amblyope is only partially effective and may not help after the end of a “critical period” for 8 years.

In a new study, neuroscientists at MIT and Dalhousie University show that by temporarily anesthetizing the retina of the good eye, they could permanently improve the vision of the amblyope, even after the critical period in two different species of mammals.

The encouraging results support further preclinical testing of the new therapy, in which the retina of the non-amblyopic eye is temporarily and reversibly silenced by an injection of tetrodotoxin (TTX), said Mark Bear, Picower professor of neuroscience at the Picower Institute for Learning and Memory. at MIT and corresponding author of the study published in eLife.

“We observed recovery in every animal,” says Bear, a faculty member in the Department of Brain and Cognitive Sciences at MIT. “We did a lot better than anyone imagined.

The results give hope that the approach can eventually be transferred to people, adds Kevin Duffy, professor in the Department of Psychology and Neuroscience at Dalhousie.

“This is remarkable data that demonstrates an unmatched recovery profile,” says Duffy, who co-led the study with Ming-fai Fong, a postdoctoral fellow at the Bear’s Picower Institute lab. “I am optimistic that this study may pave the way for a new, more effective approach to the treatment of amblyopia. I am very proud to have been part of this enriching collaboration.

A new approach to amblyopia

The new approach is based on decades of underlying neuroscience discoveries led by Bear that revealed how amblyopia develops. When input from an amblyopic eye is weak, key connections, or “synapses,” in neural circuits leading from the eye to the visual cortex of the brain fade through a process he discovered called “long-term depression.” term”. But theoretical and experimental studies in his lab have also shown that the complete but temporary suspension of visual input creates a condition in which synaptic connections can strengthen completely, almost as if they are being “restarted.”

In 2016, Bear, Duffy, Fong and their colleagues showed that they could restore vision in amblyopic mice after the critical period by temporarily inactivating both retinas with TTX, but in the new study, they set out to determine whether the vision could recover by temporarily suspending retinal activity in just the non-amblyopic eye in older animals, Fong says.

“These differences may seem small, but they are important for several reasons,” she says. “First, inactivating both retinas effectively eliminates vision; even temporary, this presents some practical challenges. Therefore, our ability to limit inactivation to a single eye makes it potentially more treatable for clinical translation. Second, there is currently no treatment for adult amblyopia in humans. In our study, we used mature amblyopic animals that are recalcitrant to any other treatment due to the decline in plasticity that comes with age.

The authors also sought to confirm their result in more than one species to ensure that the effect generalizes to the brain of mammals. There are good reasons to think so. Clinical observations in humans show that in some cases, when a person with amblyopia loses their non-amblyopic eye due to disease or injury, their amblyopic eye may improve even though they are adults. .

In the new study, the team therefore tested whether administering TTX to the non-amblyopic eye of animal models would produce a complete recovery of the visual response in their amblyopic eye beyond the critical period. Not only did he do this on every animal tested, but also, the visual responses always returned to normal levels in the eye that received the TTX.

“This is a very clear demonstration of how understanding the principles of synaptic plasticity can produce a novel therapeutic strategy,” said Bear.

The researchers even showed that the neurons that relay visual inputs to the visual cortex, which shrinks with amblyopia, were able to return to normal size.

The effect of therapy was stronger and more consistent than in human clinical cases of non-amblyopic eye loss, because once synaptic connections are restarted for the amblyopic eye and retinal activity returns to the non-amblyopic eye. amblyopic, they reinforce each other, says Bear. .

The results support the theory that temporary inactivation of the non-amblyopic eye paves the way for permanent strengthening of synapses in the amblyopic eye. This theory argues that when activity is completely absent from the non-amblyopic eye, the degree of entry through the amblyopic eye becomes sufficient to trigger synaptic enhancement, or “long-term potentiation.”

Next steps

The theory, however, does not need to be resolved for the promising results to take the next steps towards clinical use, the authors note. Instead, Bear says he plans to pursue further studies to ensure the approach would be safe and effective for people such as adults for whom patch therapy is no longer plausible.

Besides Fong, Duffy and Bear, the other authors of the article are Madison Leet and Christian Candler of the Picower Institute.

The National Eye Institute in the United States, the Canadian Institutes of Health Research and the JPB Foundation supported the research.

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