Next-gen Alzheimer's drug targets brain enzyme

Researchers at the Swiss Federal Institute of Technology in Lausanne and Asceneuron, a spinoff of Merck Serono, have discovered a key targeting mechanism to fight the buildup of amyloid plaque in the brain thought to cause early-onset Alzheimer's, and to do so with minimal side effects.

Amyloid peptides are broken down into smaller fragments in healthy brains to play a functional role in neuron activity, but in patients with Alzheimer's disease, these small proteins tend to build up into a "plaque" that destroys the surrounding neurons, according to the Swiss institute. This deleterious effect has to do with the length of the protein fragments, the longer ones being more likely to cause problems.

So, to reduce the amount of plaque buildup in the brain, the scientists homed in on the enzyme responsible for breaking the proteins down, called gamma secretase, to create a "next-generation" Alzheimer's drug currently in clinical trials. The drug changes the location at which gamma secretase cuts the amyloid protein, leaving smaller fragments that are less likely to build up around neurons.

By changing the location of the enzyme this time rather than inhibiting it across the board, as was the case in a 2010 Phase III trial, the Swiss team kept side effects to a minimum. In the previous trial, gamma secretase's function was so inhibited that patients suffered gastrointestinal bleeding and skin cancer as a result. By changing its target, researchers were able to focus on the enzyme's neuron activity alone.

"We have obtained extraordinary knowledge about how gamma secretase can be modulated," Dirk Beher, Asceneuron's chief scientific officer and study co-author, said in a release. "This knowledge will be invaluable for developing even better targeted drugs to fight disease."

The biopharma division of Merck KGaA, Merck Serono, spun out Asceneuron in October last year with $6.2 million in seed funding. Asceneuron focuses specifically on drug discovery for Alzheimer's disease.

- here's the Swiss Federal Institute of Technology report

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