Despite 30 years of research, not a single therapy has been found to successfully delay or stop the progression of Parkinson’s Disease (PD), a slowly progressive disorder that affects movement, muscle control and balance.
It is the second most common age-related neurodegenerative disorder affecting about three per cent of the population by age 65, and up to 5 per cent of individuals over the age of 85.
Each potential cure for PD has to go through three clinical trial phases to test its safety, whether it shows signs of improving PD, and whether there is any meaningful benefit to people with PD.
Running a clinical trial is a huge logistical, costly, and time-consuming undertaking. For a single new therapy this process can take the best part of a decade.
“The current way we do trials in Parkinson’s is too slow and inefficient,” explained Camille Buchholz Carroll from the Applied Parkinson’s Research Group at the University of Plymouth.
“We need to develop new ways of doing trials such as the Multi Arm Multi Stage (MAMS) trial platform, which will speed up the process and bring us closer to finding a cure, faster. We have the opportunity to learn from the experience in these other conditions and design a new trial that will work for people with Parkinson’s.”
MAMS trial platforms already exist for prostate, renal, and oropharyngeal cancer and are currently being developed within the UK for other neurogenerative disorders such as progressive multiple sclerosis (PMS) and motor neuron disease (MND).
MAMS trials test many potential therapies in parallel (multi-arm), transitioning seamlessly through various phases (multi-stage), i.e., from a phase II safety and efficacy study to a phase III trial.
Early analyses allow unsuccessful therapies to be replaced. At the interim checkpoint, ineffective arms can be dropped and replaced by new treatment arms, thereby allowing for the continuous evaluation of interventions.
Dr. Carroll and colleagues explore how the challenges of drug selection, trial design, stratification and outcome measures, type and stage of PD to be tested have been met in promising MAMS trials instituted to address other diseases including the STAMPEDE trial; Motor Neuron Disease Systematic Multi-Arm Adaptive Randomized Trial (MND SMART]; and UK MS Society’s 2018-2022 Research Strategy.
“There are many promising drugs in the pipeline that have potential to slow down the progression of PD but taking that hypothesis to the test is still a long and cumbersome process,” notes Prof. Bas Bloem, co-editor-in-chief of the Journal of Parkinson’s Disease.
“The new approach described holds great promise for facilitating this complex procedure, so that we can gather the necessary evidence for new treatments much quicker than before. Patients will certainly applaud this development as well!”
The authors stress that to maximise the potential of a MAMS platform trial running over many years and interrogating many research questions, it is crucial that there is a pipeline in place that will continuously identify and evaluate suitable drug candidates.
Furthermore, outcome measures have to be chosen that are sensitive enough to changes in disease progression over interim stages as well as the full duration of the trial.
Other studies are taking different approaches to relieve the symptoms of Parkinson’s disease. For example, biomedical engineers at Duke University have used deep brain stimulation based on light to treat motor dysfunction in an animal model of the disease.
Succeeding where earlier attempts have failed, the method promises to provide new insights into why deep brain stimulation works and ways in which it can be improved on a patient-by-patient basis.
“If you think of the area of the brain being treated in deep brain stimulation as a plate of spaghetti, with the meatballs representing nerve cell bodies and the spaghetti representing nerve cell axons, there’s a longstanding debate about whether the treatment is affecting the spaghetti, the meatballs or some combination of the two,” said Warren Grill, the Edmund T. Pratt, Jr, school distinguished professor of biomedical engineering at Duke.
“But it’s an impossible question to answer using traditional methods because electrical deep brain stimulation affects them both as well as the peppers, onions and everything else in the dish. Our new light-based method, however, is capable of targeting just a single ingredient, so we can now begin teasing out the individual effects of activating different neural elements.”
“Neurons being stimulated with optogenetics don’t generally respond very quickly, and it seemed to me that the researchers [in a previous study] were flashing their lights faster than the neurons could keep up with,” said Grill. “The data bore this out, as the neurons appeared to be responding randomly rather than in sync with the flashes. And previous research that we conducted showed that random patterns of deep brain stimulation are not effective at relieving symptoms.”
It took more than a decade for Grill to be able to test his theory, but two recent developments allowed him to follow his hunch. Researchers developed a faster form of optogenetics called Chronos that could keep up with the speeds traditionally used in deep brain stimulation.
And Chunxiu Yu, a research scientist with expertise in optogenetics, joined Grill’s laboratory. Also contributing to the work in Grill’s laboratory were Isaac Cassar, a biomedical engineering doctoral student, and Jaydeep Sambangi, a biomedical engineering undergraduate.
In the new paper, Yu embedded the Chronos optogenetics machinery into the subthalamic nucleus neurons of rats that have been given Parkinson’s disease-like conditions in one-half of their brains. This model helps researchers determine when a treatment is successful because the resulting physical movement symptoms only occur on one side of the rat’s body.
They then delivered deep brain stimulation using light flashes at the standard 130 flashes per second.
As Grill first suspected nearly 15 years ago, the technique worked, and the rats’ physical symptoms were substantially alleviated.
Perhaps the most important result is simply that the technique worked at all. Besides offering a much clearer look at neural activity by removing electrical artifacts, the ability to deliver deep brain stimulation to precise subsets of neurons should allow researchers to begin probing exactly which parts of the brain need to be stimulated and how therapies might be tailored to treat different motor control symptoms on a case-by-case basis.
As their next experiment in this line of research, Grill and his colleagues plan to recreate this same study but in the hyperdirect pathway – the spaghetti instead of the meatballs – to see what its individual contribution to relieving symptoms might be.
Elsewhere, Parkinson’s disease researchers have used gene-editing tools to introduce the disorder’s most common genetic mutation into marmoset monkey stem cells and to successfully tamp down cellular chemistry that often goes awry in Parkinson’s patients.
The researchers used a version of the gene-editing technology CRISPR to change a single nucleotide – one molecule among more than 2.8 billion pairs of them found in a common marmoset’s DNA – in the cells’ genetic code and give them a mutation called G2019S.
In human Parkinson’s patients, the mutation causes abnormal over-activity of an enzyme, a kinase called LRRK2, involved in a cell’s metabolism. Other gene-editing studies have employed methods in which the cells produced both normal and mutated enzymes at the same time. The new study is the first to result in cells that make only enzymes with the G2019S mutation, which makes it easier to study what role this mutation plays in the disease.
“The metabolism inside our stem cells with the mutation was not as efficient as a normal cell, just as we see in Parkinson’s,” says Marina Emborg, professor of medical physics and leader of University of Wisconsin-Madison scientists , whose work is supported by the National Institutes of Health.
“Our cells had a shorter life in a dish. And when they were exposed to oxidative stress, they were less resilient to that.”
The mutated cells shared another shortcoming of Parkinson’s: lacklustre connections to other cells. Stem cells are an especially powerful research tool because they can develop into many different types of cells found throughout the body.
When the researchers spurred their mutated stem cells to differentiate into neurons, they developed fewer branches to connect and communicate with neighboring neurons.
Scientists have long known that clumps of a damaged protein called alpha-synuclein build up in the dopamine-producing brain cells of patients with Parkinson’s disease. These clumps eventually lead to cell death, causing motor symptoms and cognitive decline.
“Once these cells are gone, they’re gone. So if you are able to diagnose the disease as early as possible, it could make a huge difference,” says LJI research assistant professor Cecilia Lindestam Arlehamn, Ph.D., who served as first author of a new study co-led by scientists at the La Jolla Institute for Immunology (LJI) which adds increasing evidence that Parkinson’s disease is partly an autoimmune disease.
The research could make it possible to someday detect Parkinson’s disease before the onset of debilitating motor symptoms–and potentially intervene with therapies to slow the disease progression.
The new findings shed light on the timeline of T cell reactivity and disease progression. The researchers looked at blood samples from a large group of Parkinson’s disease patients and compared their T cells to a healthy, age-matched control group.
They found that the T cells that react to alpha-synuclein are most abundant when patients are first diagnosed with the disease.
These T cells tend to disappear as the disease progresses, and few patients still have them ten years after diagnosis.
The researchers also did an in-depth analysis of one Parkinson’s disease patient who happened to have blood samples preserved going back long before his diagnosis.
This case study showed that the patient had a strong T cell response to alpha-synuclein ten years before he was diagnosed with Parkinson’s disease. Again, these T cells faded away in the years following diagnosis.
“This tells us that detection of T cell responses could help in the diagnosis of people at risk or in early stages of disease development, when many of the symptoms have not been detected yet,” says professor Alessandro Sette who co-led the study.
“Importantly, we could dream of a scenario where early interference with T cell responses could prevent the disease from manifesting itself or progressing.”
Sulzer added: “One of the most important findings is that the flavour of the T cells changes during the course of the disease, starting with more aggressive cells, moving to less aggressive cells that may inhibit the immune response, and after about 10 years, disappearing altogether.
“It is almost as if immune responses in Parkinson’s disease are like those that occur during seasonal flu, except that the changes take place over ten years instead of a week.”
Here in the UK, neuroscientists at York University have found five different models that use types of non-motor clinical – such as sense of smell, frequently dozing off or thrashing about during dreams – as well as biological variables to more accurately predict early-stage Parkinson’s disease.
Their five-model analysis is one of the first utilising only non-motor clinical and biologic variables. Some models performed better than others but all distinguished early stage (preclinical) Parkinson’s disease from healthy, age-matched controls, with better than 80 per cent accuracy.
The models may assist in more timely administration of future treatments as they become available, according to the study published in Frontiers in Neurology today.
In the study, two separate analyses were conducted: one for the classification of early Parkinson’s disease versus controls, and the other for classification of early Parkinson’s versus SWEDD (scans without evidence of dopamine deficit).
The term SWEDD refers to the absence, rather than the presence, of an imaging abnormality in patients clinically presumed to have Parkinson’s disease.
Facilitated and more accurate prediction of early-stage, de novo Parkinson’s can allow those positively diagnosed to adopt lifestyle changes such as regular physical exercise early on that can improve mobility and balance, says Joseph DeSouza, associate professor of the Department of Psychology at York University.
Researchers used cross-sectional, baseline data from the Parkinson’s Progressive Markers Initiative (PPMI).
The PPMI data used was confined to non-motor clinical variables (e.g. sense of smell, daytime sleepiness, presence of rapid eye movement behaviour disorder, age, etc.) and biologic variables (e.g. cerebral spinal fluid alpha-synuclein, tau protein, beta-amyloid-142, etc.)
Five different model types were “trained” models that could prove useful in helping to differentiate early stage Parkinson’s pathology.
