In the wake of the failure of the investigational drug solanezumab, which stirred the debate over whether the prevailing amyloid theory of Alzheimer’s disease is still a viable working hypothesis, ProMIS Neurosciences announced their contribution to Alzheimer’s amyloid-related drug development.
The announcement was accompanied by a commentary interpreting the failure of certain drugs — and offering an explanation of how ProMIS’s drug development efforts differ from others targeting amyloid-beta to slow or prevent Alzheimer’s disease.
According to the company, the earlier drug candidates failed to work because they targeted single soluble amyloid-molecules — so-called monomers — or large aggregates known as plaque.
Amyloid-beta is produced as a single molecule, but is prone to attached itself to other amyloid molecules. In recent years, research has shown that it is not the monomers nor the plaques that are toxic to neurons. Instead, it is an intermediate between the two that causes harm, consisting of aggregates holding only a few amyloid-molecules.
Research has also shown that these smaller aggregates, known as oligomers, are also capable of triggering amyloid-beta aggregation in nearby areas. For this reason, ProMIS refers to them as prions, and they are not alone in interpreting Alzheimer’s in this way.
Prions are abnormal proteins that make other nearby proteins take on the same unnatural features. This induces a spread of diseased proteins throughout the brain. Prions are the cause of diseases such as Creutzfeldt-Jakob disease, in which the brain degenerates.
ProMIS products, which so far have only been tested in lab-grown cells, only bind amyloid oligomers. Also, the company states that their products are the only ones that can identify the site and shape of misfolding of the amyloid proteins to allow a specific targeting of misfolded prion forms of amyloid-beta.
ProMIS candidates were tested in a cell assay that mimics the way amyloid aggregates and spreads throughout the brain. Tests showed that all five lead candidates, as well as back-up compounds, completely or nearly completely prevented all stages of the spread.
“These results further validate our approach to developing an effective Alzheimer’s disease therapeutic, as blocking propagation of toxic forms of Aβ [amyloid-beta) inhibits a key process in the development and progression of Alzheimer’s disease,” Dr. Elliot Goldstein, ProMIS CEO, said in a news release.
“We previously demonstrated that the five mAb therapeutic candidates ProMIS is developing display the optimal target profile of selective binding to prion-like forms of Aβ with virtually no binding to Aβ monomer or plaque,” added Dr. Neil Cashman, chief scientific officer of ProMIS.
ProMIS believes that because of the specific mechanisms, their candidates are both more effective against disease and safer than drugs currently in development. For instance, they mention the risk of brain swelling caused by the removal of plaque by Biogen’s aducanumab.
The company is conducting further studies of their compounds’ abilities to prevent amyloid-beta neurotoxicity. They hope the studies will enable the selection of a drug candidate to bring to clinical trials.
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