Antihistamines halt Huntington's Disease
Huntington’s is a horrible, inherited neurodegenerative disease. The symptoms normally begin to appear in a person’s 30s and include abnormal movements and cognitive changes. They’re caused by the progressive loss from the brain region known as the striatum of a population of neurones that respond to the nerve transmitter chemical dopamine. Blocking dopamine to reduce the activity in the cells can produce some symptomatic relief, but the side effects of doing this are unpleasant. Recently QMUL’s Peter McCormick has found that, alongside the dopamine receptors on the affected cells, there are also histamine receptors. And blocking those secondarily quietens the response to dopamine and in experimental mice seems to halt the progression of symptoms, as he told Chris Smith…
Peter - We discovered several years ago that the histamine receptor can modify the dopamine receptor's ability to function. So we thought, could we take advantage of that characteristic and dampen the out of control dopamine via histamine?
Chris - How does that work then - is the histamine signalling to the same cells, and it's just having an effect on the way those cells respond to the presence of dopamine?
Peter - What we think is happening is we've got a histamine radio tower right next to the dopamine one. And by targeting the histamine with a drug, we can dampen the output signal of that dopamine radio tower, which doesn't allow it to signal as well. So it's running interference basically.
Chris - And why does this ultimately translate into a benefit for the disease process?
Peter - We think it slows down the ability of dopamine to signal and those neurons don't fire as much. So they're more likely to stay alive and not die.
Chris - So the disease process is still grumbling along underneath, you haven't affected that. But what you have done is to control some of the ways in which it impacts on the vulnerability of the cells that would otherwise die.
Peter - That's correct. So we're not specifically targeting the Huntington's protein, and we're not fixing the disease, but we are able to slow progression. And the hope is because there are quite a number of histamine compounds in the clinic, they might be repurposed for Huntington's.
Chris - How did you do this though? Presumably this is not a clinical trial yet. This is preclinical animal data.
Peter - That's correct. That's correct. So we have to initially show that our idea would work and sell. So we first worked in a cellular model of Huntington's and then we later took that to a mouse model of Huntington's. And then we later showed from a brain bank, human brain bank, that the same target of these two receptors together existed early on in Huntington's patients.
Chris - So that suggests that were you to translate this to humans, because the same target's there as in your experimental animals, it should work. But what sort of difference do you get in these animals with the rodent equivalent of Huntington's disease? What sort of a difference to the outcome and clinical course does your intervention make in these mice?
Peter - Yeah. So typically in this disease, especially in the preclinical model, you start to see neuronal death very early on. You start to see cognitive problems. So they have trouble remembering, short term memory, long term memory, spatial memory, and motor problems. All of those, we were able to reverse by treating with a drug targeting the histamine receptor.
Chris - And when you say reverse, does that mean as long as the animals keep taking the drug, they just don't manifest any of the usual signs of Huntington's disease?
Peter - That's correct. We saw no development of any of the symptoms of the disease, and we didn't see any neuronal death. And what was interesting is we did a very short treatment with these animals, and yet we could still see benefits a month after we removed treatment, suggesting that an early intervention with such an approach might really provide some exciting benefits.
Chris - The problem is that people who are prescribed some of these dopamine blocking drugs, describe horrendous side effects.
Peter - Yes.
Chris - Is there a possibility though, because the histamine receptors are there for a reason in these brain cells, is there a possibility that we're just trading one set of side effects for another and your animals are still going to manifest cognitive problems or at least emotional problems, perhaps problems even staying awake because you block these receptors?
Peter - Now we didn't go in depth in terms of the side effects. And that's certainly I think one of the questions that will have to come up. We didn't see also in the control animals any cognitive changes that were unusual. There certainly will be a risk. But I think that if you speak with a lot of patients suffering from this disease, it is quite debilitating. My prediction is these side effects would be much less than targeting the dopamine receptor itself.
Chris - And is that the next step to now formally evaluate this in a clinical trial with a cohort of Huntington's patients and put them on some of these antihistamines and see if you can change the progression of their syndrome?
Peter - First what we would like to do is select the right molecule. I think the molecule we used in our preclinical experiments was very effective, but there are other candidates out there that I would like to test in a preclinical model to just really make sure that we've got the right one before we go into humans.