Parkinson’s: Why Has Disease Modification Failed — and What Now?

Researchers have made many attempts at disease modification as they pursue breakthroughs in treating Parkinson’s disease, but so far without success. Why have these efforts failed, and what’s next in treating this degenerative disorder that affects an estimated 10 million people worldwide?

We tackled these questions in a Premier Research webcast, The Potential for Disease Modifying Therapies in Parkinson’s Disease. In this blog post, the second of three on the subject, we examine these past attempts, why they failed, and what targets are currently being pursued.

Where we’ve been

Let’s start with some previous attempts at disease modification:

Selegiline is a monoamine oxidase (MAO) inhibitor that enhances dopaminergic function. It appeared promising because patients showed effects from selegiline treatment after several weeks of washout, but researchers ultimately concluded that they were seeing extended symptomatic relief rather than a true disease-modifying effect.

Exenatide, a GLP-1 agonist approved for treatment of Type 2 diabetes, was considered a candidate for protecting neurons and enhancing neuroplasticity. A small study met its primary endpoint, but inconsistency in the results called into question whether there was a true disease-modifying effect. Further research is now underway.

Levodopa, used to treat Parkinson’s symptoms for more than 50 years, also has been studied for possible disease-modifying benefits. Some patients who stopped taking levodopa for long periods showed sustained effects from the treatment. Another study, known as LEAP (Levodopa in EArly Parkinson’s disease), is now concluding and may shed interesting light on the drug’s potential.

Why have past efforts failed?

One reason past attempts at disease modification have fallen short is that, despite widespread belief to the contrary, Parkinson’s is not a single-cause disease. Phenotypic and genotypic heterogeneity among patients defies a one-size-fits-all approach, and many of the preclinical models used for Parkinson’s are not exactly transferable to the disease in humans. Consequently, early development of potential disease modification treatments might be faulty from the start.

A common issue with clinical trials is how much the targets in each study are engaged and whether the correct dose has been determined. More work is needed to identify biomarkers that track with Parkinson’s in real time so we know that they’re engaging the target and are incoincident with the impact of the therapy being used. Additionally, there is concern that some patients enrolled in previous studies who were classified as having early-stage disease may have had extensive neurodegeneration. The same challenge often bedevils Alzheimer’s research.

Current disease modification targets

The mechanism of action currently being studied most frequently — because it has demonstrated involvement in the pathology of Parkinson’s — is related to alpha-synuclein. If this synaptic protein is non-functional, it contributes to the inability of neurons to produce dopamine, the major pathophysiologic mechanism of Parkinson’s disease. An unsolved question is whether, in neurons, there is a loss of function or a direct toxicity resulting from the non-functionality of synuclein.

Other therapeutic strategies are being explored. One subject of several studies is monoclonal antibodies targeting the toxic formulations of alpha-synuclein. There are other attempts, like a small molecule looking at the inhibition of protein misfolding, and c-Abl inhibition using a nonreceptor tyrosine kinase enzyme to reduce oxidative stress.

Another approach is genetic stem cell therapy to rehabilitate and/or supplement the substantia nigra (SN) neurons with the goal of restarting dopamine production. The concept is fairly simple, but many challenges stand in the way of implementation. It would involve injecting stem cell-derived, dopamine-producing neurons directly into the SN to replace or restore the dopamine production function within those neurons. That would require access to the skull and a robust method to inject those neurons into the mid-brain.

And there are still more esoteric approaches, such as determining how nicotine affects Parkinson’s. It has long been known that the more patients smoke, the less likely they are to get the disease, and among those who do smoke, the condition progresses more slowly.

Our webcast examines these and other potential strategies in greater detail, so check it out. It also looks at potential future targets for Parkinson’s disease modification, and that will be the subject of the third and final installment in this series.