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- Is this the next Game Changer……..
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Is this the next Game Changer……..
Is this the next game changer? Injecting live cells to repair the damaged dorsal horn in neuropathic pain.
I am sitting in a cafe in Nice, France. The biennial NeuPSIG congress is on and it has kicked off with a bang. Allan Basbaum gave the inaugural Ed Charlton opening plenary yesterday and I confess to have been late because my own obsession with pain had me wandering the old town looking for authentic patisseries staffed by old ladies who don't speak English. French bread is clearly the best bread on the planet. The twenty minutes of Allan's talk that I got to went a bit like this (Allan would give a far better account of this and I not-very-secretly hope that this post triggers him to write a better one on the same stuff):
- The loss of GABAergic neuron inhibitory function in the dorsal horn reflects the 'disease' of neuropathic pain.
- In mice, pharmacologically administering GABA at the level of the cord is very analgesic - Allan would say 'blocks the pain' but he does not really believe that pain is blocked at this level - he actually believes that nociceptive transmission is blocked at this level and that pain is constructed by the brain. I wish he would say that because I really think it matters. But that is not the point of this post so I will drop it now.
- Pharmacologically blocking the nociceptive message is not tenable as an ongoing strategy for many reasons. The holy grail would be to repair the dorsal horn, to repair or replace the endogenous GABAergic neurones.
- A very cool study in an animal version of epilepsy had transplanted progenitor cells from embryonic brains into the epilepsy-affected mouse brain. Progenitor cells are a bit like post-graduate stem cells – cells that have already been pushed towards a particular kind of target cell, in this case they have been pushed towards becoming GABAergic cells. The amazing result? Epilepsy was “cured” because the GABAergic inhibitory control was reestablished by the new neurones.
- Allan thought 'well, neuropathic pain is like epilepsy of the dorsal horn, so why don't we inject these cells into the dorsal horn of mice with neuropathic pain to see if they will repair that too?'
- Despite suggestions that the cells 'want to be in the brain and will migrate there'*, and some other legitimate biological barriers, Allan got his team onto it. They injected 50 thousand of these cells, and waited for a month. I reckon that would have been a pretty high stress month for his team. But, 'voila!' it worked. The cells 'took', they integrated with the other cells in the dorsal horn, they migrated throughout the dorsal horn selectively NOT integrating in some laminae, which is astounding in itself, formed synapses with the host and they returned the mouse to normal on the basis of behavioural tests with nociceptive stimuli.
Think about this for a moment - the damage to GABAergic cells in the dorsal horn as a result of a traumatic sciatic nerve injury, was fixed. More recently, they showed that the same approach can overcome the mechanical hypersensitivity and heat hyperalgesia that occurs in chemotherapy-induced neuropathic pain. Seems like a game changer to me.
However, as Allan said - it is a very long way off being used in humans. He and his colleagues are now working with human stem cells modified to become GABAergic neurons and have encouraging preliminary results. The mice have no immune system, which would obviously be a problem for other reasons, to stop them rejecting the human cells. Although stem cell therapy is underway in other conditions, there are profound barriers to this type of thing happening in humans, not least rejection, the profound interactions between descending control mechanisms and the complex biopsychosociality of the human.
I chatted with a few NeuPSIG VIPs about this stuff and there was a mix of excitement - 'it's a whole new world now isn't it?' and skepticism - 'basic scientists cure chronic pain, again….'
That might be slightly harsh – I reckon Allan might argue that the basic scientists have actually cured chronic pain in a vast number of animals and animal models and that is their job. Of course, that is not really the point – it is pretty hard to argue against the benefits that have come to countless humans on the back of revolutionary discoveries in animal models. I guess those of us who sit alongside these patients and feel their despair, and would so dearly love to be able to offer them more than we can, might be protecting ourselves from hoping too much.
Enough of the self-reflective stuff – whatever your take on it, the idea of actually repairing damaged dorsal horns is bona fide new. Allan's plenary really was a superb start to what is a superb meeting.
Wish you were here? Well I'd stick Gothenburg 2017 in your diary now.
* this was very groovy stuff indeed - these cells migrate all over the brain and with some sense of order - we sure are fearfully and wonderfully complex!