Ending Parkinson’s disease: The path is getting shorter

Parkinson’s disease (PD) is a progressive neurodegenerative disorder that affects movement, resulting most notably in tremor, slow movement, stiffness and balance issues. While Parkinson’s patients benefit from medicine that can alleviate some of these symptoms, there are no available treatments to slow, halt or reverse the progressive destruction of dopamine-producing brain cells and abnormal clumping of alpha synuclein, an otherwise normal brain protein. The disease affects roughly 10 million people worldwide and is the 14th leading cause of death in the United States.

While the research community continues to deepen its understanding of how to stop Parkinson’s disease, there’s consensus that the genesis of the disease is rooted in a misfolded protein that become toxic to the brain. Protein misfolding is common in the body; It’s normal for proteins to misfold on a daily basis. A healthy body simply corrects the misfolding and moves on. However, as the body ages, it becomes less equipped to correct the misfolding; this is when toxicity can occur.

Two decades of searching identifies a root cause

Protein misfolding is at the root of several neurodegenerative diseases, including Parkinson’s, Alzheimer’s and ALS (amyotrophic lateral sclerosis or “Lou Gehrig’s disease”). In Parkinson’s disease, the misfolding process occurs within alpha-synuclein, a brain protein with natural protective properties. However, when α-synuclein misfolds, it can create toxic aggregates (clumps) called toxic oligomers. These errant proteins are adept at converting other healthy forms of α-synuclein to toxic forms, and can propagate through the brain, killing neurons in their path. Identifying this process as a root cause of Parkinson’s disease was the breakthrough result of two decades of research beginning with the discovery of genetic links between α-synuclein and the risk of developing Parkinson’s disease. Researchers have also determined that the toxic oligomeric version of otherwise normal protein in the brain was at the root of several other neurodegenerative diseases. The protein misfolding process is the same; the brain protein affected is different.

Identifying a root cause of Parkinson’s gave researchers a viable target for drug development efforts. However, drug developers learned quickly that targeting the toxic forms of α-synuclein and only the toxic forms is challenging. Toxic oligomers contain unstructured regions and are relatively unstable. It is for this reason that traditional methods are unable to develop antibodies with adequate precision to selectively target these toxic forms. Rather, these methods produce antibodies that also bind to the many other normal variants of α-synuclein. This is problematic because new data show one form, in particular, α-synuclein tetramer, performs a protective function in the brain and must be preserved.

At the end of March, scientists engaged in neurodegenerative disease research worldwide will gather in Lisbon at AD/PD, the international conference on Alzheimer’s and Parkinson’s disease. At this conference, researchers will highlight their progress toward therapies for these diseases. Several of these therapies are promising. However, antibodies created using traditional development methods may lack the level of selectivity the toxic oligomer requires. New tools for developing antibody therapy candidates are needed for this very unique target.

The role of supercomputing in drug development is an exciting new trend, particularly in neurodegenerative diseases. In Parkinson’s disease, supercomputing combined with world-class biology and physics offers researcher a new way to make drugs that can selectively target the toxic forms of a α-synuclein while preserving the normal forms. AD/PD will highlight several new potential antibody candidates for Parkinson’s disease that can block the toxic forms of a-synuclein while preserving the normal forms better than antibody drug candidates in development.

The ability to target the root cause of neurodegenerative diseases with precision will continue to capture headlines as drugs in development take aim. Drug development for Alzheimer’s disease, which is more mature than that for Parkinson’s disease, has suffered numerous failures. There’s new opportunity to avoid this outcome for Parkinson’s disease. And quite honestly, we can’t afford it. Parkinson’s patients are in a vulnerable state when they are diagnosed. Symptoms do not occur until 80 percent or more of the midbrain’s capacity to produce dopamine is lost. By contrast, Alzheimer’s disease patients retain 90 percent of their brain’s function when symptoms first appear. Drug developers urgently need new tools to develop drugs to avoid the same disappointing trajectory as Alzheimer’s disease.

New developments coming out of AD/PD suggest we won’t have to. Today’s drug discovery methods have developed some wonderful medicines, but for the toxic oligomer, they deliver drug candidates that are as imprecise as a shotgun. New approaches can deliver drug candidates that act like a sniper. This allows exacting precision on the toxic oligomer, reducing the potential for side effects related to targeting the non-toxic forms of proteins in the brain. This kind of precision hasn’t been available before and the hope is that it will shorten the path to treatment not only for Parkinson’s disease but for a host of other neurodegenerative diseases that remain without effective treatments.

Neil Cashman is a neurologist, academic director, Vancouver Coastal Health ALS Clinic, Vancouver, British Columbia, and chief science officer, ProMIS Neurosciences, Inc.

Image credit: Shutterstock.com

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