Tetrodotoxin Explored as a Treatment for Amblyopia

Article: Novel approach reverses amblyopia in animals
Source: Picower Institute at MIT
Published: September 1, 2021
Article: Pufferfish Toxin Holds Clues To Treating 'Lazy Eye' In Adults
Source: NPR
Published: September 15, 2021

Amblyopia results when there are underdeveloped connections between the eye and the brain, and can have etiologies ranging from congenital cataracts to strabismus (an eye misalignment), to anisometropia (unequal refractive state), all of which prevent the affected eye from resolving clear images to form the necessary neural connections. The predominant view is that there is a critical period during childhood after which amblyopia cannot be reversed, even after the underlying etiology is corrected. Aside from behavioral approaches, clinicians have relied on "patching" of the unaffected eye with the thought that the affected eye would form stronger synapses with the brain. This "patching" can be a physical patch over the eye, the same concept of which is retained in more recent uses of atropine eye drops to blur vision in the unaffected eye. Neuroscientists exploring ways to reverse amblyopia have found success in a novel approach, namely, by injection of tetrodotoxin (TTX), which temporarily (reversibly) anesthetizes the retina of the unaffected eye. Experiments in two animal models (mice and cats) have produced "an unequaled profile of recovery" in the amblyopic eye even after the critical period. This recovery was seen in every animal they tested. At the neurological level, synapses that are weak wither in a process known as "long-term depression." However, the researchers explain that temporarily, but completely, suspending visual input creates a condition in which the synaptic connections can fully restrengthen, as if being “rebooted.”

Fellow eye inactivation promotes stable functional and structural
recovery in cats following long-term monocular deprivation

In an earlier study from 2016, the researchers showed that they could reverse amblyopia by anesthetizing both retinas. In the present study, they were able to limit the effect of TTX to the retina of only the non-amblyopic eye. Additionally, the current study was conducted in mature amblyopic animals that were not responsive to other forms of treatment. The scientists even observed that neurons that shrink with amblyopia regained normal size after treatment. Finally, in addition to improving vision in the amblyopic eye (i.e., reversing amblyopia), visual responses recovered to normal levels in the eye that received the TTX in every animal tested, demonstrating no lasting negative effects. It should be noted that a major difference between this approach and prior variations of "patching" is in the complete inactivation of vision that triggers strengthening of synapses in the affected eye. The researchers will pursue further studies to explore tetrodotoxin as an option for adults who suffer from amblyopia. As co-lead author of the study remarks, “I am hopeful and optimistic that this study can provide a pathway for a new and more effective approach to amblyopia treatment. I am very proud to have been part of this rewarding collaboration.”

My rating of this study: ⭐⭐

Fong M, Duffy KR, Leet MP, et al. "Correction of amblyopia in cats and mice after the critical period." eLife.  410:e70023. 31 August 2021. https://doi.org/10.7554/eLife.70023