MISSISSAUGA, Ontario—ProMIS Neurosciences Inc. recently announced that they have identified several potential antibody therapeutic candidates aimed at selectively targeting toxic oligomers of the protein α-synuclein, which is considered a root cause of Parkinson’s disease (PD) and is linked to Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS) as well. While the root causes of these related neurodegenerative diseases remain disputed, several studies definitively implicate toxic oligomers in the development and progression of PD.
ProMIS began looking at the toxic oligomer based on research linking it to Alzheimer’s disease. Alzheimer’s drug developers have predicated most new treatments on the long-held “amyloid hypothesis.” This popular theory—with roots that date back more than 100 years—held that amyloid beta, a naturally occurring substance that forms clumps in the brain, could become dangerous for some people as they age, much like how a normal cell might become cancerous. The amyloid hypothesis held that sometimes these clumps—commonly called “plaques”—would strangle brain cells, leading to their death and eventually, disease onset. Drug developers erroneously believed that by targeting plaque in the brain, they could develop a therapy that would halt Alzheimer’s disease, but 25 years of drug development were derailed when it was proven that plaque itself does not cause AD, thus raising doubt about the amyloid hypothesis.
According to ProMIS President and CEO Dr. Elliot Goldstein, however, knowledge of AD has deepened in some important ways: “New understanding of amyloid demands a version 2 of the amyloid hypothesis. We now know there are several kinds of amyloid in the brain, but only one form is toxic, the toxic oligomer. This understanding is facilitating a radical shift in AD drug development, with a new generation of drug development efforts that target the toxic oligomer.”
ProMIS launched their Parkinson’s program because significant data also implicate the toxic oligomer for PD as well as for ALS. For Parkinson’s, they are targeting the toxic oligomer that derives from alpha synuclein, a naturally occurring protein. Despite broad evidence linking the toxic oligomer to neurodegenerative diseases, the challenge has been how to selectively target it for antibodies. The toxic oligomer is a highly unstable shape-shifter, making it very difficult to isolate. ProMIS applied its thermodynamic, computational discovery platform—ProMIS and Collective Coordinates—to predict novel targets known as disease-specific epitopes on the molecular surface of misfolded proteins.
“Using our unique discovery platform, we were able to identify several novel targets displayed on toxic oligomers of α-synuclein and generate antibody candidates capable of protecting brain neurons against such toxic oligomers in vitro,” stated ProMIS Executive Chairman Eugene Williams. “We now look forward to further validation and selection of the most promising candidates to move forward in development for PD. We see our emerging Parkinson’s disease program as an ideal pharma partnering opportunity.”
Working with the French contract research organization Neuron Experts, they investigated the neuroprotective effect of ProMIS’ antibodies on rat primary dopaminergic neurons injured by exposure to toxic oligomers of α-synuclein, an in-vitro model of PD. In the test, several ProMIS antibodies that selectively target toxic oligomers of α-synuclein significantly blocked the death of neurons induced by these oligomers.
Commenting on these results, Goldstein stated: “We feel our patented discovery platform represents the future of drug development for neurodegenerative diseases. It marries physics with medicine, granting us the unique ability to light up new targets on the toxic oligomer, test and validate hundreds of antibody drug candidates against these targets, and then rapidly progress the strongest candidates across the finish line.”
Using their precision medicine approach, ProMIS is developing novel antibody therapeutics for AD, ALS and PD. They also hope the technique can eventually be applied to neurodegenerative diseases in general, spinal muscle atrophy, Huntington’s disease and other dementias, such as Lewy Body dementia, frontotemporal dementia and prion disease. They also see an opportunity to explore the platform’s potential in chronic, sports-related head trauma, called chronic traumatic encephalopathy.
While the latest release focuses on the progress ProMis has made looking at Parkinson’s, they intend to aggressively pursue a treatment for Alzheimer’s using the platform. According to Goldstein, they intend to look at other potential AD culprits as well.
“Our long-term goal is to develop therapies that pack a one-two punch for AD and ALS,” he noted. “Regarding AD, we know that toxic oligomers of the protein Tau also play a causal role in disease progression; we’ll target Tau next.”