Evolution of a memory drug for Down’s syndrome

A couple of months ago I broke a story for New Scientist about clinical trials of the first drug specifically designed to tackle learning impairment in Down’s syndrome. It was published online on 11th April, and a cut down version appeared in the magazine’s InBrief section on the 20th ( pdf available on request). But news stories being what they are, where space is limited and average attention spans are pandered to, some interesting detail didn’t make the cut in either version, so I thought I’d take the opportunity to elaborate here…

So how did this drug come to exist? And how exactly does it work?

Professor David Nutt, who is acting as a consultant on the trial, explained the history of the drug – RG1662, which is an alpha-5 inverse agonist of a neurotransmitter called GABA – in some detail.

Neuroscientists have long known that drugs which enhance the effects of GABA tend to “calm the brain down”, because GABA inhibits, rather than excites, brain activity. The hippocampus is a brain region that plays a central role in the formation of memories, so if GABA activity in the hippocampus is enhanced enough, memory is impaired. Valium – a benzodiazepine – is an example of a drug that does this.

Substances that enhance activity are called agonists, and there are also antagonists, which block these effects by binding to the relevant receptor without activating it, effectively taking it “out of play”. These two effects have been know about for many decades, but over the past several years a third type has emerged. These substances are known as inverse agonists, because they cause the opposite effect to an agonist. This is possible because many receptors have a certain level of activity before anything binds to them, so a substance that reduces this will produce the opposite effect to one which increases it. Both agonists and reverse agonists are blocked by antagonists.

Benzodiazepines are GABA agonists. Antibenzodiazepines are inverse agonists for GABA, so scientists wondered whether they might improve memory. Unfortunately, GABA is involved in so many different things that if you “turn it down” throughout the brain you get serious side effects such as anxiety and even seizures. The area stalled there for a while, but breakthroughs in genetics have since revealed a range of different GABA receptors in the brain. There is one, called the “alpha-5-containing receptor”, found primarily in the hippocampus that is particularly involved in memory. Pharmaceutical companies promptly began looking for drugs which only affect this type of receptor.

And sure enough, a few years ago Merck managed to find just such a drug and were developing it for memory impairment in old age. Unfortunately it caused kidney problems so the company killed development and stopped making the drug available for research. Just before it was killed however, Nutt managed to study it and found that it “completely normalised memory function” in people intoxicated with alcohol. After seeing these results a group of French researchers gave the same drug to mutant mice whose memory was impaired by the mouse equivalent of Down’s syndrome and found their memory was also returned to normal. The race was on to find a variant with the same effects on memory, without such undesirable side effects.

Now Roche seem to have found exactly that, and Nutt is working with them on a dose-finding trial. This will pave the way for a full clinical trial to test whether it can truly improve memory function, and hence treat learning impairment, in people with Down’s syndrome. Of course there is a bit more to learning than just memory, but committing new information to memory is the central feature of learning, and people with Down’s also tend to show impaired memory, so there is every reason to hope this drug might eventually enable them to lead more independant lives.

Nutt presented these revelations in a presentation at the BNA13 Festival of Neuroscience in which he also made a more general point. He thinks we are potentially on the brink of a revolution in the treatment of many genetic disorders of the brain. Other examples include Fragile X and Rett syndromes, and tuberous sclerosis. “There are a lot of neurodevelopmental disorders that are genetic – we know the genes, we can make mutant mice with those abnormalities, and study new treatments,” he says.“So there’s a lot of interest in treating developmental disorders – either to stop them early, or reverse them in adulthood.” But treating developmental disorders early raises practical and ethical questions. Researchers can’t begin testing drugs on children – adults have to be studied first, to allow for informed consent. Then there are questions around whether it’s ever ethical to give drugs to children, and whether parents with the syndrome would want to give consent.

Then of course, there’s the ethical and political implications of this story. Advances in screening for Down’s have reached the point of certainty, giving women the option to terminate their pregnancy early if they so choose. The possibility that one day we may be able to educate Down’s children alongside everyone else is pure speculation for the moment, but the promise of a normal education, and the independence that could bring, certainly has the potential to cast this moral dilemma in an entirely new light. Depending of course, on the results of clinical trials such as this.

 

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