Planning For Prevention. It Is Time.
Preparing to prevent Parkinson’s might seem premature. After all, even when scientists wistfully describe the ‘holy grail’ of PD therapeutics, we typically aspire to halting or perhaps reversing the inexorable clinical decline. Of course simply slowing progression of disability would represent an epic achievement. If we have yet to demonstrate that any treatment can dent progression in people already diagnosed with PD, is it wise to start designing trials to disrupt PD development in healthy people? I believe the answer is now yes. For two good reasons:
1. Our ability to identify who is at higher risk of getting PD has rapidly expanded. This growing capability will soon allow us to define populations of healthy individuals who are sufficiently ‘at-risk’ to justify joining clinical trials of candidate protective therapies, at least those that are reasonably safe. The opportunity results from an accelerating understanding of PD risk factors – both genetic determinants and prodromal features of the disease.
Genetically defined at-risk groups – Although most people with PD do not have a relative with the disease, a small percentage of PD runs in families because of particular gene mutations and we are learning very quickly how to spot them. Several of these mutations like those in the PINK1, DJ1 and Parkin genes almost invariably lead to PD (i.e., are highly penetrant) but are far too rare to warrant a systematic prevention trial. Conversely, variants of genes like SNCA or MAPT are quite common but have very low penetrance, and so these too are not suitable for therapeutic trials. However, there are a couple PD genes – GBA and LRRK2 – whose mutations can be sufficiently common and penetrant to be considered as candidate targets.
Healthy carriers of a potentially pathogenic mutation in the LRRK2 gene are emerging as a prototypic population for testing preventative strategies. Although the best characterized LRRK2 mutations account for only about 1% of PD, carrying such a mutation puts one at substantial (~25-75%) risk over a lifetime. Through major biomarker and clinical characterization endeavors like the LRRK2 Cohort Consortium (LCC) and the Parkinson’s Progression Marker Initiative (PPMI) of the Michael J. Fox Foundation, fairly large cohorts comprising hundreds of currently unaffected LRRK2 mutation carriers are being assembled across the globe. Not surprisingly, these at-risk individuals are highly motivated to contribute to PD therapeutics research given the potential future benefit for themselves and for their already affected loved ones as well as children and grandchildren at genetic risk.
Clinically defined at-risk groups – In parallel to the explosion of genetics progress in PD a tsunami of pathological and clinical discovery has been quietly building in recent years. This wave of insight has flowed from mechanistic theories of abnormal spread of a PD-linked protein (α-synuclein) to and through the brain, and has facilitated the demonstration that α-synuclein-linked symptoms often precede the onset of PD’s classical movement disorder by years. These prodromal PD features can include gut dysfunction manifesting as constipation, a reduced sense of smell (hyposmia), and sleep disruption by dream enactment (REM sleep behavior disorder, or RBD). On their own these can be modestly (constipation) to moderately (RBD) predictive of developing the disease. However, in combination they may be powerfully predictive of PD. Accordingly, it’s been proposed that screening large healthy populations using simple, inexpensive assessments for these features could identify a sizable group of individuals with multiple prodromal features at markedly increased PD risk.
Recent studies have shown that at-risk genetic (LRRK2) or clinical (hyposmic) cohorts can be enriched even further using brain scans that track dopamine-producing brain cells and possibly with fluid (e.g., blood, cerebrospinal fluid) biomarkers of PD. And so, taking a page from research on Huntingon’s disease, another neurodegenerative disorder for which prevention trial strategies are being actively designed and implemented with genetically at-risk individuals, PD research is poised to begin planning for prevention trials on those who are at risk based on genetic and/or clinical predictors.
Charlie Shepiddy, motivational mascot of the ongoing SURE-PD3 trial of inosine as a candidate neuroprotective therapy
2. The other major impetus to begin planning for PD prevention trials, alas, is born of failure, namely all the unsuccessful clinical trials of candidate neuroprotectants. To date none of the dozen or so advanced clinical trials of proposed protectants has provided clear evidence of favorably modifying the disease course even when tested at the earliest ‘de novo’ stage following diagnosis (though two ongoing phase 3 trials with novel targets and designs – STEADY-PD III and SURE-PD3 – remain promising). Just as in the Alzheimer’s disease field, where similar setbacks left a wake of ineffective medications for slowing dementia and led to trials at a pre-dementia stage, so too should we consider moving earlier in the disease process in PD. Given the evidence that half of all dopamine-producing brain cells have already degenerated by the time a patient is diagnosed with PD, the idea of intervening earlier ‘before the horse is out of the barn’ makes increasing sense for trials intended to ‘close the barn doors’ on the neurodegenerative process.
While we should begin investing in pre-PD trial development, there are still challenges to overcome before we can launch the first rigorous PD prevention trials. Beyond selecting at-risk populations to target, we must determine which potentially protective drugs or non-pharmacological strategies (like specific nutritional or exercise interventions) to test. Their risks generally should be lower than those considered acceptable for people with manifest PD. Perhaps most challenging is what to actually measure. Unless we are able to target at-risk individuals on the cusp of diagnosis, true prevention trials would likely require too much time (many years if not decades) or too many volunteers (hundreds if not thousands). Changes in dynamic biomarkers that reflect early disease process (e.g., scans of dopamine-producing brain cell integrity) or a drug target’s engagement may be suitable even if yet to be validated.
Planning for protection trials also requires us to overcome a psychological hurdle in redirecting our attention to treating healthy people. As clinicians, family members and patients in the PD community we’re understandably focused on those who battle the disability of PD on a daily basis. We tend to view prevention as less pressing than modifying manifest disease. Arriving at the dentist in pain is not the best time to read a brochure on fluoridation to prevent tooth decay. Nevertheless, as a community we should – because we now can – turn some of our attention to the emerging opportunity for Parkinson’s prevention.
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Michael Schwarzschild, MD, PhD has presented at each World Parkinson Congress since 2006, and served on the WPC 2013 and WPC 2016 steering committees. Michael is a Professor and Julieanne Dorn Chair of Neurology at Harvard Medical School, and conducts basic and clinical research at the MassGeneral Institute for Neurodegenerative Disease. He chairs the Executive Committee of the Parkinson Study Group (PSG), a non-profit consortium of North American clinical investigators conducting trials of candidate Parkinson’s therapies for over 30 years. He cares for people with Parkinson’s at his clinic at Massachusetts General Hospital.
Ideas and opinions expressed in this post reflect that of the author(s) solely. They do not necessarily reflect the opinions or positions of the World Parkinson Coalition®