Megan Brooks

July 20, 2015

WASHINGTON ― Novel compounds showing early promise for Alzheimer's disease (AD) target multiple disease-related proteins and may have benefits beyond AD, according to research presented here at the Alzheimer's Association International Conference (AAIC) 2015.

Alzheimer's is a complex disease that has been hard to tackle with the "one target, one treatment" approach, Maria Carrillo, PhD, chief science officer for the Alzheimer's Association, said in statement.

"Fortunately, we're beginning to see some very exciting early results at AAIC 2015 of a new treatment approach that targets common components of all the Alzheimer's proteins, which also are common to other diseases that cause dementia. If these results can be shown in people, this strategy could eventually have benefit not just in Alzheimer's but for other neurodegenerative diseases," she noted.

Potential Game Changer?

In a poster, Fernando Goni, PhD, of New York University School of Medicine, in New York City, and colleagues report that a class of monoclonal antibodies known to target both tau and amyloid in AD also react to aggregated alpha-synuclein and Lewy bodies in brain cells of people with Parkinson's disease.

The investigators tested three monoclonal antibodies against single alpha-synuclein proteins, oligomeric alpha-synuclein proteins, and dense fibrillar forms known to accumulate in brain tissue.

They found that all three bind to the oligomeric forms of alpha-synuclein but not to the monomeric forms. Using samples of human brain tissue from Parkinson's patients, they confirmed the antibodies' affinity for alpha-synuclein-related structures in neurons.

"We have developed monoclonals that recognize the commonalities in many neurodegenerative diseases," Dr Goni told Medscape Medical News.

"Because they mainly see the toxic oligomers independently of the disease, we think we can attack all of them, because we tested the monoclonals with brain tissue of actual Alzheimer's, prion, and Parkinson's diseases, and they saw structures related to all these pathologies. On top of that, in an AD mouse model of both culprits ― amyloid and misfolded tau ― the pathology was reverted. If we are lucky, the same can happen in other disease using the same monoclonals."

"We are trying to secure support to eventually start clinical trials once all the animal testing is completed. Because of the nature of the monoclonals, this can be a game changer in the therapeutic future of neurodegeneration," Dr Goni said.

Important New Approach

In an oral presentation, Richard Fisher, PhD, of NeuroPhage Pharmaceuticals, Cambridge, Massachusetts, reported early results with a novel first-in-class drug candidate for AD now called NPT088, which targets misfolded disease-related proteins, including aggregates of both amyloid-beta and tau.

NPT088 prevents protein aggregation in laboratory-cultivated brain cells and helps brain cells survive after exposure to toxic aggregated proteins. NPT088 also shows beneficial effects in transgenic mice with brain damage akin to that seen in patients with AD and Parkinson's disease, "in most cases improving memory and cognition and reducing the brain levels of amyloid beta, aggregated tau, and alpha-synuclein," according to a conference statement.

"NPT088 effectively treats brain pathologies in mouse models of both Alzheimer's and Parkinson's disease, which we believe is unique for a drug candidate," Dr Fisher added in a conference statement.

NPT088 is in the final stages of animal safety testing. "Pending regulatory approval, we plan to begin clinical testing in people with Alzheimer's in early 2016," Dr Fisher said.

Another compound generating buzz here is TRV 101, a small molecule that also targets protein misfolding.

Using computer modeling techniques, Marcia Taylor, PhD, from Treventis Corporation, Toronto, Ontario, Canada, and colleagues screened more than 11 million compounds and identified a family of compounds that inhibit toxic protein-protein interactions. TRV 101 is one of the most promising compounds and the "most developed" thus far, Dr Taylor noted in an interview with Medscape Medical News.

TRV 101 has optimum druglike properties, including "high brain penetrance and oral bioavailability and is benign in a 44-receptor panel test," the investigators report in their poster.

In a test tube model, TRV 101 binds to both beta-amyloid and tau and prevents them from aggregating and misfolding.

"This could allow natural clearing mechanisms to remove existing protein aggregates and improve cognitive function. We are currently testing our compounds in animal models to verify if we can reduce the levels of oligomers in the brain," Dr Taylor said in a statement.

There is a growing "consensus that Alzheimer's will be treated like AIDS is treated, with a combinatorial approach, but we are able to do a combinatorial approach in one pill," she told Medscape Medical News.

"Targeting multiple disease-related proteins is an important new approach. If you think about what we are doing today, we are really targeting Alzheimer's disease with one target, one drug, and we see a potential for incremental benefit, but we are going to need a combination approach. All major diseases that have been successfully treated or cured have had a combination therapy approach. Alzheimer's is not going to be any different," Dr Carrillo told Medscape Medical News.

"The really cool thing," added Dr Carrillo, "is that today we are looking at a variety of different approaches, and this discovery science is teeing off what we can potentially see as a future therapy."

Dr Goni's research was supported by the National Institutes of Health, the Alzheimer's Association, and the Seix Dow Foundation. Dr Fisher's research was supported by NeuroPhage Pharmaceuticals and the Michael J. Fox Foundation. Dr Taylor's research was supported by the Wellcome Trust and the Toronto General and Western Hospital Foundation.

Alzheimer's Association International Conference (AAIC) 2015. Posters P4-174 and P1-307; oral presentations O1-0501 and P2-324. Presented July 19, 2015.

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