MDS 2022 | α-synuclein & Parkinson’s disease: moving away from anti-α-synuclein approaches?
Alberto Espay, MD, MSc, University of Cincinnati, Cincinnati, OH, comments on the results from two recent clinical trials evaluating anti-α-synuclein immunotherapy approaches for the treatment of Parkinson’s disease. Both trials included agents targeting the aggregated form of α-synuclein, and while the trials were supported by robust evidence, the outcomes of both were negative, contradicting the results hypothesized. Therefore, it is essential to rethink the relationship between α-synuclein and disease; perhaps focus on the loss of normal proteins rather than the abnormal aggregation, and shift towards the replacement of α-synuclein instead of the anti-α-synuclein approach. This interview took place at the 2022 International Congress of Parkinson’s Disease and Movement Disorders in Madrid, Spain.
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Transcript (edited for clarity)
There have been two clinical trials recently reported that work on eliminating the aggregated form of synuclein. And it turns out that in both cases, the drugs came into trials with a robust evidence that they actually do so. And so these trials were done with the idea of testing the hypothesis that an anti-synuclein approach such as that afforded by these immunotherapies could in fact bring on benefits...
There have been two clinical trials recently reported that work on eliminating the aggregated form of synuclein. And it turns out that in both cases, the drugs came into trials with a robust evidence that they actually do so. And so these trials were done with the idea of testing the hypothesis that an anti-synuclein approach such as that afforded by these immunotherapies could in fact bring on benefits. And the outcome of both was in fact negative.
The assumption is made that perhaps target engagement, which is impossible to measure because we don’t have a radioligand that can capture the insoluble fraction of synuclein in the brain, prevents us from determining whether there was any target engagement, whether in fact we were able to reduce the insoluble levels of synuclein. But the evidence is that even with that gap in our knowledge, the results aren’t moving in the direction that we hypothesized.
And as such, I think is important for us to rethink the relationship between synuclein and disease, and perhaps to think that synuclein is in fact quite important for the brain. It’s all over the body, brain included. And once we lose it because it’s becoming entrapped in insoluble amyloids, it no longer can provide its function. And so the loss of the normal protein may in fact be much more relevant than the accrual of the insoluble fraction of the protein, what we call Lewy pathology. This is consistent with the fact that there has been no relationship between the burden or the distribution of Lewy pathology and the clinical features or the degeneration in the brain. So it’s important that all levels of evidence are converging on the concept that losing synuclein may be much more important than eliminating the aggregated fraction of the protein. And perhaps these two trials will make us move away from an anti-synuclein approach and begin to consider the possibility that perhaps there is much to be gained by testing the idea of replacing the levels of normal synuclein to levels that can be more functional to the brain.
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Disclosures
Prof. Espay has received grant support from the NIH and the Michael J Fox Foundation; personal compensation as a consultant/scientific advisory board member for Abbvie, Neuroderm, Neurocrine, Amneal, Acadia, Acorda, Kyowa Kirin, Sunovion, Lundbeck, and USWorldMeds; honoraria from Acadia, Sunovion, Amneal, USWorldMeds; and publishing royalties from Lippincott Williams & Wilkins, Cambridge University Press, and Springer. He cofounded REGAIN Therapeutics, owner of a patent application that covers synthetic soluble non-aggregating peptide analogs as a replacement treatment in proteinopathies. He serves on the editorial boards of the Journal of Parkinson’s Disease, Journal of Alzheimer’s Disease, European Journal of Neurology, and JAMA Neurology.
