Clinical Research: Phase 1 - Phase 4

Finding the Path to Disease Modification in Parkinson’s Disease

Among common degenerative disorders, Parkinson’s disease strikes more frequently than all but one: Alzheimer’s. Parkinson’s affects about 1 percent of the population over age 60 and claims 60,000 new diagnoses in the United States each year.[1]

The cause of Parkinson’s remains a mystery, and the dopamine promoter levodopa — notwithstanding its limitations — has been the principal treatment for about half a century. But researchers are making headway in discovering potential mechanisms of disease modification, and that’s the subject of our latest webcast, The Potential for Disease-Modifying Therapies in Parkinson’s Disease, with Andreas Schreiner, MD, Premier’s Executive Director, Medical Affairs, Medical Services; and Barry Dussault, Senior Director, Program Delivery, Neuroscience, Premier Research.

In this first of three posts on the subject, we provide background on Parkinson’s, identify some of today’s open questions in clinical research, and take a first look at disease modification strategies.

Background of Parkinson’s disease

This chronic progressive disorder affects not only the dopaminergic neurons of the substantia nigra, but also involves numerous other genetic and molecular entities and affects both the central and peripheral nervous systems. It’s associated with a wide spectrum of motor and non-motor features, and dopamine deficiency is just one of several commonalities.

Typical symptoms are postural instability, falls, speech and swallowing difficulties, autonomic dysfunction, psychosis, and dementia. Within 15 to 20 years of onset, the mortality rate is two to three times that of the general population.

Open questions in Parkinson’s disease

Researchers today are addressing some very important open questions:

  • Does onset occur early or late, and can we somehow predict the disease in people who are at risk?
  • What is the underlying pathology and the individual role of various mechanisms such as synaptic transmission, endosomal sorting and maturation, lysosomal degradation, and mitochondrial biogenesis, individually or in combination?
  • Are there distinct Parkinson’s subtypes?
  • Are specific disrupted cell pathways truly pathogenetic, compensatory, or even protective?

Disease modification strategies in Parkinson’s

The most promising treatment approaches involve changing the clinical course of Parkinson’s through disease modification. Those most actively under study are:

Compensation, which you might think of as “disease modification light.” It involves supporting the failing compensatory mechanisms for the dopamine deficiency that causes Parkinson’s and related degenerative changes. This is probably the most achievable method of disease modification but remains a formidable challenge.

Neuron rescue is the next level of disease modification. One of the causes of Parkinson’s is the death of neurons that produce dopamine. Neuron rescue would involve salvaging some of the dying neurons by reversing their metabolic abnormalities or giving them trophic support.

Neuron restoration is the most ambitious and challenging approach. Potential methods include neuro restoration, using cell-based therapies to replace or restore some of the degenerative neurons.

Another approach, of course, would be to prevent Parkinson’s from occurring in the first place, but that requires an understanding of the disease we do not yet have. Short of that, we could delay the onset of the disease after it has started or slow — or perhaps even stop — its progression. Unfortunately, we are currently limited to very blunt assays in this research, and that restricts our insight to clinical (motor and non-motor) and surrogate parameters such as neuroimaging. These can have a weak correlation with actual disease progression and/or may trail the progression so that any blunt indications we observe fall behind the actual symptomatic effects on patients.

Interpretation of these results is also confounded by the therapies currently used, chiefly levodopa. There are ethical issues in withdrawing patients even from therapies with limited efficacy to enroll them in clinical trials. The ideal solution would be a measure that coincides with the modification of the disease independent of symptomatic treatments in more or less real time.

It’s a complicated field of study with implications for millions of Parkinson’s patients worldwide. In our next post, we’ll look at past attempts at disease modification and at what research is currently in progress. For more information on disease modification in Parkinson’s, contact us today.

[1] Parkinson’s Foundation. Statistics. Published August 7, 2018. Accessed November 20, 2018.