Amblyopia, commonly referred to as lazy eye, is a vision disorder caused by an imbalance in the connections to the visual cortex. Many of us probably know someone with amblyopia or are affected ourselves, as it is nearly impossible to treat after early childhood (Hamilton, 2021). But in some cases where affected adults lose their “good” eye, they regain vision in their amblyopic eye. How can that be?
Well, we have known for years that the brain is remarkably plastic and constantly rewiring itself. In fact, similar results have been observed in monkeys and cats that have had their unaffected eye removed. But losing an eye is a high price to pay just to regain vision in the other. What if instead, you just tricked the brain into thinking that the dominant eye was lost?
It turns out you can do that with tetrodotoxin (TTX), a neurotoxin commonly found in a particular variety of puffer fish. TTX inhibits voltage-gated sodium channels. If sodium can’t enter the neuron, it can’t generate an action potential, which renders it incapable of sending signals. As you might imagine, this can have potentially fatal consequences at high doses (think respiratory failure). But at low doses, the effects are reversible, and a group of researchers at MIT figured out how to exploit that.
By injecting a small amount of TTX into the unaffected eye of cats and mice with amblyopia, Fong et al. demonstrated that you can temporarily inactivate that eye, and effectively convince the brain that it is missing. It only inactivates the eye for about 1 to 2 days, but that’s all the time the brain needs to start rewiring itself. The underlying biological mechanisms are not well understood, but the prevailing hypothesis is that there is potentiation of excitatory synapses feeding the amblyopic eye. This could mean changes in things like NMDA receptors or inhibitory signals, but the bottom line is that potentiation is occurring and having lasting effects (Fong et al., 2021).
Overall, the results of this study are a testament to the plasticity of the adult brain, and even though this method has not yet been tested in humans, the replicability across mice and cats suggests that it could one day be a viable treatment option for amblyopia and perhaps other neurological conditions.
References
Fong, M.-fai, Duffy, K. R., Leet, M. P., Candler, C. T., & Bear, M. F. (2021). Correction of amblyopia in cats and mice after the critical period. ELife, 10. https://doi.org/10.7554/elife.70023
Hamilton, J. (2021, September 15). Pufferfish toxin holds clues to treating 'lazy eye' in adults. NPR. Retrieved September 21, 2021, from https://www.npr.org/sections/health-shots/2021/09/14/1037096390/pufferfish-toxin-holds-clues-to-treating-lazy-eye-in-adults.
Galen,
ReplyDeleteThis is honestly pretty cool. Who would've thought that marine life could possibly be the cure for lazy eye?!
I wanted to know a little bit more about TTX and I found this article that goes into some detail about the toxin and how it affects humans. I also found that the marine life acquire this by their diet and that they are immune to the neurological effects. Regarding humans, TTX has been shown to cause different grades of effects.
Grade 1 including tingling, mouth numbness, and possibly GI upset. Grade 2 including numbness of the face, slurred speech, motor paralysis, and some incoordination. Grade 3 including loss of speech, paralysis, respiratory failure, and dilated pupils. Grade 4 including respiratory failure with hypoxia, hypotension, cardiac abnormality regarding arrhythmia, and unconsciousness.
Looking at this layout of possible effects, how is it that we should go about administering the correct doses to patients? Do you think that it is safe to begin trials on humans?
Kotipoyina HR, Kong EL, Warrington SJ. Tetrodotoxin Toxicity. [Updated 2021 Aug 11]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK507714/
Hi Gia,
DeleteI think we’re years away from trialing this in humans, but as with most investigational drugs, researchers would probably start with a sub-therapeutic dose to assess the safety and tolerability and go from there. Overall, I think the safety of it rests on two things: localization and dose. In the referenced experiment, they injected the TTX directly into the vitreous humor of mice and cats, so its effects were contained to the unaffected eye. Moreover, toxicology studies have demonstrated that TTX is eliminated quickly and is undetectable in plasma within 24 hours (Hong et al., 2017). So while TTX is highly toxic, it is dose-dependent, and I suspect that the dose required to inactivate just the unaffected eye would be significantly lower than the LD50. With it being derived from fish, though, I am not sure how it would be regulated, which is what Kat brought up in her comment below.
Hong, B., Chen, H., Han, J., Xie, Q., He, J., Bai, K., Dong, Y., & Yi, R. (2017). A Study of 11-[³H]-Tetrodotoxin Absorption, Distribution, Metabolism and Excretion (ADME) in Adult Sprague-Dawley Rats. Marine drugs, 15(6), 159. https://doi.org/10.3390/md15060159
Hey Galen,
ReplyDeleteGreat application to an interesting topic from class! However, the risk involved seems like it may outweigh the benefits. I was curious about the cost analysis of using TTX verses common treatments. Mild cases of Amblyopia seems to be treated fairly easily using eye therapy (less than $2000 without insurance) or even just using an eye patch if caught young enough. However, the most applicable population would be adults who need to get surgury which can cost upwards of $10k (https://spendonhealth.com/lazy-eye-surgery-cost/).
While I may not have perfect understanding, it seems like the proposed TTX would assist those with milder cases (that 1-2 day range) opposed to the severe cases that need invasive work. As a result, I am curious of TTX would be cheap enough and controlled enough to be a liable option.
Hi Kat,
DeleteYou raise some great points about cost and control – I have no idea how much it would cost to isolate or synthesize TTX, nor how it would be regulated. Those things aside, though, I think this method offers some benefits that surgery and patching cannot.
As you mentioned, patching can be an effective treatment option for patients under 10, but studies have also found that recurrence happens in more than 25% of patients (Bohla et al., 2006). I suspect that part of the reason why some relapse is that it isn’t inducing permanent changes. Despite being covered, the unaffected eye is likely still communicating with the visual cortex, even if it’s just “background noise”. And if you think about how your eyes move in tandem, just covering the eye likely isn’t enough to convince your brain that it’s missing.
Another cool aspect of this study is that there is electrophysiological and behavioral evidence that complete recovery persists weeks after the TTX wears off (Fong et al., 2021). So it seems like whatever potentiation cascade is initiated by TTX is not inhibited by the regain of function in the good eye.
Obviously, there is a lot more research that needs to be done before they test this in humans, but I do think it could be a less invasive alternative that induces more permanent changes.
Bhola, R., Keech, R. V., Kutschke, P., Pfeifer, W., & Scott, W. E. (2006). Recurrence of amblyopia after occlusion therapy. Ophthalmology, 113(11), 2097–2100. https://doi.org/10.1016/j.ophtha.2006.04.034
Fong, M.-fai, Duffy, K. R., Leet, M. P., Candler, C. T., & Bear, M. F. (2021). Correction of amblyopia in cats and mice after the critical period. ELife, 10. https://doi.org/10.7554/elife.70023