To Predict and Prevent
When you have a problem, it’s best to remedy the cause rather than the symptoms….otherwise any fix will temporary and could lead to more problems. In Parkinson’s disease (PD) we currently have medications for ‘symptomatic benefit’ but none that slow or halt disease progression. Clinical trials of new medications, largely informed by toxin-induced models of disease, have failed. Dopamine replacement therapy remains the best drug to help with movement initiation but many motor and non-motor features remain. Its benefits are also temporary; increased doses of medication are required to prevent ‘wearing off’ and can result in dyskinesias.
So how can genetics help? Consider a car’s engine as an analogy for PD enabling the car’s motion. When the engine doesn’t start, or fails to work optimally, it’s best to do some diagnostics. Is it the distributor, the battery, the spark plugs etc? Although the physiology of cortical-striatal-midbrain (nigral) circuits in PD is well described, our knowledge of underlying cellular and molecular problems…the smaller parts of the engine…and why some get PD and others are spared…is rudimentary. Genetic research can fill this gap.
Although funding agencies/industry invest huge amounts in clinical trials in PD, given the promise of great return, they had scant knowledge of its molecular cause(s). Nevertheless, to predict and prevent disease i.e. for pharmaceuticals to be neuroprotective, they should target the cause. In early 1997, when I started my career, ‘prevailing wisdom’ suggested genetic analysis in PD was a futile endeavor. It had long been described as a sporadic disease, due to environmental exposures rather than genes, despite ~14% of patients having an affected first-degree relative. Disease concordance in monozygotic twins was quite low/negligible. Nevertheless, health and disease are biological traits and must have some genetic contribution 1.
At that time I had just joined Mayo Jacksonville where Dr. Manfred Meunter, formerly Chair of Neurology at Mayo Scottsdale, told me of a family with multi-incident parkinsonism-dementia, first seen at the Clinic in the early 1920’s 2. With a little reading I became aware of many other families in which PD appeared as a heritable trait, passed from one generation to the next. In 1880, 1883, Charcot, the grandfather of French neurology, encouraged and supported two of his students to study familial ‘paralysis agitans’. Allen, 1937, working in the Carolina’s, identified and published many pedigrees with multi-incident PD. In 1940, Henry Mjones documented familial parkinsonism throughout Sweden etc.
Thus, one dark, rainy winter’s evening, I came to meet members of the Spellman-Meunter kindred, (named after the neurologists who had first described the family’s plight). I wanted the family’s blood for DNA studies, their clinical data and most importantly their approval to find the gene I thought may be responsible for their disease. Anguished sobbing came from within the house as a couple of biker’s swiftly answered the door. The ‘angels’ barked at me to go out back where I leant they had been running from parkinsonism-dementia, ‘the bug’, for generations. They had been told the cause was environmental. Their mum was crying, helping to care for her ~30 year old son while his young children…the next generation… played on the floor. She had lost her husband in the same circumstance, to the same malady, 30 years prior. It was tragic. In this family, parkinsonism starts in the fourth decade and leads to dementia and ultimately death within about a decade. That night I made a first promise to find the cause and figure out a remedy.
It took several more years of painstaking research, fieldwork to track down relatives throughout the US, genotyping and linkage analysis. Finally, despite the early pessimism of the field and grant funding agencies, we discovered alpha-synuclein (SNCA) multiplication as the cause3. Most people have 2 copies of the gene (human beings are diploid, one set of chromosomes from Dad, one set from Mum) whereas clinically affected members of this family had 4 SNCA copies. We discovered more families with parkinsonism due to 3 SNCA copies, albeit with a less aggressive, later-onset phenotype4,5. Indeed, in work begun by Henry Mjones in the 1930’s, in the best described SNCA multiplication family, we found patients with 4 copies who developed early-onset parkinsonism and those with 3 copies who had late-onset parkinsonism6. In human brain we showed SNCA genomic copy number, gene and protein expression levels were correlated7. We also appreciated that common variability throughout SNCA is a modest a risk factor for sporadic PD8–10, for its motor progression11 and for subsequent dementia12.
Antibodies to alpha-synuclein had been found to stain Lewy pathology, the aggregate inclusions within neurons long considered as a defining feature of post-mortem PD13. Braak’s subsequent ‘staging scheme’ revealed their spread, appearing to ascend from the gut via the vagal nerve to the brainstem and then cortex13. Lewy-like inclusions can also be induced from a ‘host’ with PD to young neurons transplanted in embryonic nigral grafts14. We now know induction and propagation of specific, toxic oligomeric conformations of alpha-synuclein can be modelled, via direct injection, in brain15,16. Nevertheless, there is still little correlation between Lewy body burden and dopaminergic neuronal loss17. Typically, pathology is the consequence of a disease process rather than its cause. In addition, in late-stage PD the relationship between Lewy pathology, cognitive decline and dementia has yet to be resolved18.
If alpha-synuclein genomic dosage is associated with autonomic, motor and cognitive symptoms, age of motor symptom onset and its progression, it occurred to me that we might prevent disease and/or slow its course…at least in subjects with SNCA multiplication…if we simply lower SNCA gene expression. However, to develop such a drug would take major pharmaceutical investment. As companies will not invest unless they can be legally assured of their rights to ownership Mayo Clinic patented the idea (US patent W0 2005/004794 A2). To encourage industry to embrace the notion, and with Michael J Fox Foundation support, we also started working to lower alpha-synuclein expression with early success in mice19 and non-human primates20 using RNA interference as a method of gene silencing.
Nevertheless, many obstacles lessened enthusiasm of the Pharmaceutical industry. First, PD is still considered a dopaminergic movement disorder. In reality, it affects multiple neurotransmitters leading to a multi-faceted syndrome with motor and non-motor problems. Despite wearing off and side-effects, dopamine-replacement (L-DOPA) does give immediate, measurable, symptomatic benefit even if it fails to halt progression. It’s the yardstick to which any new drug is compared. Hence the US Food and Drug Administration had to accept neuroprotection (disease-modification) as an adjunct therapy. Second, is how gene silencing might be delivered to the brain, as charged molecules fail to penetrate the blood-brain barrier. Third, is which subjects would be best to inform a neuroprotection trial? Fourth, is how neuroprotection might be measured? Clinical trials are typically <2 years and there are no biochemical biomarkers of progression.
While these problems were daunting for most we now have solutions. For example, small molecules such as antisense oligonucleotides to specifically lower gene expression can be delivered by an intrathecal route, with an implanted catheter and using a refillable mini-pump21. This is no more invasive that surgeries to implant electrodes for deep brain stimulation (DBS), a safe effective and relatively common procedure in PD, and might even be done at the same time. Alternatively, adeno-associated virus is a safe/effective method to deliver genetic material in human brain, and may be used to irreversibly lower endogenous gene expression22,23. On which individuals would best inform a clinical trial, and how might efficacy/neuroprotection be quantified, the answers may be sought in subjects with SNCA multiplication mutations. In such individuals we can best predict the age of onset and disease progression, even before symptoms arise. We know the cause of disease, we understand the precise mechanism, and lowering alpha-synuclein levels would be the best remedy to halt and perhaps prevent parkinsonism and associated Lewy body dementia.
Of note, several companies are planning to lower alpha-synuclein protein expression, albeit using immunologic approaches, either vaccine-based or with intrathecal injections of alpha-synuclein antibodies, focusing on idiopathic PD24. A vaccine approach was first conceived by the late and great Dale Schenk, to help clear brain amyloid in dementias25,26. Whether the therapy will be successful in sporadic Alzheimer’s disease (AD) remains to be proven, and how a Phase III efficacy trial might best be designed is critical. Which choice of which subjects are best to treat, when, for how long, and what should be the outcome measures for success? In AD, amyloid deposits occur decades prior to developing any clinical symptoms, and by the time patients are diagnosed it may be too late. Longitudinal decline in cognitive function is challenge to accurately quantify, and peripheral biomarkers are limited. With the exception of rare families with amyloid precursor protein (APP) mutations, amyloid deposits may be a downstream consequence of the condition rather than causal. Results in SNCA families, including study of novel peripheral biomarkers for alpha-synuclein27, would inform trials in idiopathic PD and could leverage and inform prior work by the Michael J. Fox Parkinson’s Progressive Markers Initiative.
The scientific merit, feasibility and need is most acutely recognized by families with SNCA multiplication, their neurologists and medical geneticists. Thus, together we have convened a global SNCA Multiplication Consortium to help enable a safe, ethical and pragmatic remedy. We are currently working with ~60 multi-incident families and are looking to identify additional medical professionals and subjects with SNCA multiplication mutations (http://geopd.can.ubc.ca/projects/6). Global participation for the project is enabled by regional coordinators including Profs. Nobutaka Hattori and Beomseok Jeon in Asia, Prof. Alexis Brice in Europe and Prof. Matt Farrer (the author) in North America. We are also looking to partner with non-profit Foundation’s and industry that are committed to developing therapeutics for Parkinson’s disease, due to alpha-synuclein pathology.
It is true that the majority of patients with PD do not have a heritable disease in the classical Mendelian sense. Even those with greatly elevated risk due to a single mutation in alpha-synuclein (SNCA), leucine-rich repeat kinase 2 (LRRK2), vacuolar protein sorting 35 (VPS35) or glucocerebrosidase (GBA) etc. may not develop symptoms in their lifetime (reduced penetrance). However, genetic variability plays an important part in whether, what, and when, symptoms manifest. Genetics helps to explain why the disease ontology of every patient with Parkinson’s disease is unique and how they respond to drug therapy. The pharmaceutical industry and clinical trials are now starting to use genetic information to find and target the underlying cause(s) of parkinsonism, not just the symptoms (http://www.alzforum.org/news/research-news/large-phase-2-trial-starting-genetic-parkinsons-population). Such therapeutic development, while still unconventional, is most likely to be effective and might be used in combination with conventional dopamine replacement. A genetic foundation gives me high hope for the success of these trials!
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Matthew Farrer, PhD presented at the 1st World Parkinson Congress in Washington DC; the 2nd World Parkinson Congress in Glasgow, Scotland; and the 3rd World Parkinson Congress in Montreal, Canada. He is a Professor in the Department of Medical Genetics at the University of British Columbia, the Canada Excellence Research Chair, and the Don Rix BC Leadership Chair in Genetic Medicine.
Ideas and opinions expressed in this post reflect that of the authors solely. They do not reflect the opinions or positions of the World Parkinson Coalition®