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Will multipronged AD attack be more successful?


By Anette Breindl
Senior Science Editor

Claude-Henry Volmar is no longer particularly surprised when clinical trials of drugs for Alzheimer's disease (AD) fail.

And fail they do, basically without fail. The most recent casualty to join the lengthy list of drugs that have no significant effect on AD was Axovant Sciences Ltd.'s intepirdine, (RVT-101), which missed its co-primary efficacy endpoints in the MINDSET trial in patients with mild to moderate AD who were receiving background donepezil therapy. (See Bioworld, Sept. 27, 2017.)

Intepirdine's failure was noteworthy mainly because it was not aimed at amyloid beta, which has been the target of dozens of failed trials. The drug was supposed to work by blocking 5-HT6 serotonin receptors.

Volmar, who is a senior scientist at the University of Miami Medical School's Center for Therapeutic Innovation and associate director of the Sylvester Molecular Therapeutics Shared Resource, and his colleagues said they think the root of the problem lies not with any one target.

In their opinion, the issue lies with focusing on only one target in the first place.

"We're thinking it's mostly because Alzheimer's is polygenic – many genes are involved," Volmar told BioWorld. "One target, one disease doesn't work in Alzheimer's."

In the Oct. 9, 2017, issue of the Proceedings of the National Academy of Sciences, Volmar and his team published preclinical results testing an alternate approach.

In mouse models of Alzheimer's disease, treatment with the histone deacetylase (HDAC) inhibitor M344 affected multiple genes that have been implicated in AD.

HDACs affect the epigenetic tags that determine whether a gene is silenced or repressed, which means that by using an epigenetic drug, "we can [simultaneously] modulate a lot of Alzheimer's genes," Volmar explained.

In cell culture experiments, the team showed that the drug affected the expression of both risk genes and beneficial genes, and the net effect of treatment was to "move the pendulum towards the protective side," Volmar said.

Protective genes that were up-regulated included brain-derived neurotrophic factor (BDNF), "which was up-regulated a lot and has been shown to be protective in Alzheimer's," Volmar said.

Another enzyme that was up-regulated was alpha-secretase, which processes amyloid precursor protein (APP) in an alternate pathway to beta- and gamma-secretase. More alpha-secretase activity reduces the amount of amyloid beta by sending APP down that alternate path.

In behavioral experiments, the team showed that daily treatment with M344 could prevent behavioral decline and normalize memory in transgenic mouse models of both early onset and late-onset AD.

The work now published in PNAS focused more on prevention, but the researchers are also working on using HDAC inhibitors later in the course of the disease, when symptoms are already apparent.

Multiple targets also means multiple opportunities for on-target toxicity, and preventive treatment, which by its nature is long term, gives all the more opportunity for toxicities to arise. But for the time being, the researchers have observed no such toxicity.

Volmar attributed the low toxicity to several different causes.

The effective dose for treating AD mice turned out to be much lower than that which is required in oncology, where HDAC inhibitors are also used and toxicity has been an issue.

Also, the goals of treatment with a HDAC inhibitor are different in AD than in cancer.

In cancer, he said, the "mindset is to increase exposure to kill cells." In AD, the goal is to rewire cells to a degree, but "you don't want constant presence of the drug there."

M344, he noted, rapidly penetrated the brain and was rapidly metabolized.

"It presents low toxicity because it doesn't stay in the system long enough," he said. "Within 30 minutes it's gone, which means that daily treatment is feasible.

"It is a common belief that if you have a lot of targets, you'll cause toxicity," as he summarized his team's experience. "But what we are seeing is that that's not necessarily true."