In The Field

Neuroscience 2008: New ‘epigenetic’ memory drug

Michael Ahlijanian, a vice-president of the small biotech company EnVivo, told the meeting that the company’s new compound EVP-0334 is to enter clinical trials for treating memory disorders ‘very soon’. That it has made it so far is surprising and scientifically interesting, particularly since it acts by interfering with epigenetic phenomena in the brain.

This small molecule blocks a class of enzymes called histone deacetylases. These enzymes strip acetyl groups from histone proteins surrounding tightly coiled strands of DNA. Acetyl groups mark the DNA for unwinding so that genes can be exposed for transcription. By stopping the enzymes from working, EVP-0334 promotes a looser DNA structure and thus more gene expression.

According to Ahlijanian the compound enhances long-term and short-term memory in mice – not in all memory tasks though. It’s very robust in object recognition tests, good but less robust in spatial recognition tests and it does not affect other aspects of memory like contextual fear conditioning. He also says that it showed no toxicity in the mice at high doses for 28 days.

That’s the interesting thing. Why not? Histone deacetylase inhibitors don’t feel intuitively very selective. After all, they keep open those stretches of DNA tagged with acetyl groups, exposing lots of genes. Ahlijanian said that ‘only’ 5% or fewer genes were affected by EVP-0334 – but that’s a hell of a lot. Yet the response in the mice seems to be very specific – and no-one gets close to clinical trials without good toxicology data. Ahlijanian doesn’t have the answer – he doesn’t even know for sure yet which are the relevant genes activated by the drug — but he speculates that it may be down to regional distributions of relevant gene promoters.

Histone deacetylase inhibitors are already used in cancer therapies but those in the clinic do not get into the brain. EVP-0334 passes the blood-brain barrier. If it really does get into clinical trials it’ll be a welcome new addition to the list of hopefuls for Alzheimer’s disease and other disorders of memory, and one with a novel mechanism. That’s of course a long way off. In the meantime it will be extremely interesting to follow how the science of its mechanism unfolds.

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