Named after English surgeon James Parkinson, best known for his book ‘An Essay on the Shaking Palsy’ – a clinical account on the disabling condition that causes motor impairment – Parkinson’s disease was first described as a neurological syndrome in 1817. However, ancient Indian texts and Chinese sources also chronicled what seemed to be descriptions of Parkinson’s disease, back in 1000 BC.
Its distinction from other tremorous disorders, specifically multiple sclerosis, came after French neurologist Jean-Martin Charcot, who also gave the disease its name, derived that not all individuals with Parkinson’s disease experience tremors.
Researchers were also able to distinguish between Parkinson’s disease and Parkinsonism – an umbrella term used for neurological disorders similar to Parkinson’s, often characterized by tremors, slow movement and stiffness.
Soon after its diagnosis was established, therapeutic interventions began making its way, with Charcot’s plant-based hyoscyamine, an anticholinergic agent – a drug that blocks the action of the neurotransmitter acetylcholine in the central nervous system (CNS) – being used to control tremors and reduce muscle stiffness.
Then, in the 20th century, dopamine-based therapies began gaining popularity, with the breakthrough Parkinson’s drug levodopa drawing attention. As a temporary replacement for dopamine – a neurotransmitter that declines in Parkinson’s – levodopa eases motor symptoms caused by the disorder. Although, side effects to the drug like nausea and dizziness have been recorded, and its prolonged use has caused motor issues for some patients.
Over the years, surgery has been made a viable option as well, with deep brain stimulation turning heads in therapeutic studies.
However, as the disease affects about 10 million people around the world, with the prevalence expected to double within the next 20 years, there is an unmet need for therapeutic measures; which researchers are working towards accomplishing.
As we observe Parkinson’s Awareness Month in April, here are five advancements in Parkinson’s disease research that could revolutionize therapeutic studies.
Focused ultrasound: a novel therapy for Parkinson’s with tremor
The novelty of focused ultrasounds has not worn off; in fact, the rapidly evolving technology has been making headlines of late after researchers at the University in Chapel Hill (UNC) School of Medicine led a clinical trial to demonstrate that the treatment improved motor impairment in people with Parkinson’s disease, a research that was published in February 2023.
The therapy also aims to tackle dyskinesias, which are involuntary movements – twitches, jerks, twisting or writhing movements – of the face, arms, legs or trunk, which are observed in some patients with Parkinson’s disease who have been on the oral treatment levodopa – which tops up dopamine levels in the brain and alleviates some of the diseases’ symptoms – for a long time.
The trial conducted by UNC, which assessed 94 Parkinson’s disease patients, saw that 75% of those who underwent focused ultrasound treatment, maintained positive results for around a year after the treatment was completed. Apart from patients achieving improvement in motor function and reduced dyskinesia, the treatment also eliminates the risk associated with surgery, as the procedure is incisionless.
Earlier, surgical procedures like thalamotomy and pallidotomy, where a lesion is made in the thalamus or the pallidum regions of the brain, particularly for patients who experience tremor – a symptom resulting in an involuntary quivering movement that affects 80% of people with Parkinson’s – were recommended. However, as the procedure aims to cut an opening in the thalamus, thereby damaging part of the brain, methods like focused ultrasound have become more appealing, according to Julie Pilitsis, neurosurgeon at Marcus Neuroscience Institute in Florida, who specializes in functional neurosurgery.
“Rather than inserting something in the brain, you go into the MRI…Because now, you don’t have to have open brain surgery for this,” said Pilitsis.
“This is particularly attractive for people – when they’re older, they don’t want to do a surgery, and I totally get that.”
Deep brain stimulation and gene therapy for Parkinson’s make headway
Having been around since 1997 to treat Parkinson’s tremor, deep brain stimulation (DBS) was approved in 2002 to treat the symptoms of advanced Parkinson’s disease and then again in 2016, to address earlier stages of the condition, for those individuals whose motor symptoms are entirely controlled with medication. More recently, DBS has gained attention as a potential precursor for stem cell therapy and gene therapy for Parkinson’s disease.
Some studies have even considered the possibility for gene therapy to be used in combination with DBS to replenish dopamine levels in the brain. According to Pilitsis, in the future, stem cell therapy and gene therapy seem promising for Parkinson’s.
“I think that’s where we kind of see the field going where electricity or ultrasound is our tool right now. But we see those tools as getting more advanced over time,” she said.
Much like a pacemaker, DBS stimulates certain parts of the brain through electrodes that are implanted.
Pilitsis explained the significance of directional leads which are designed to expand the capabilities of DBS by more accurately inducing stimulation. “That’s been really helpful because it’s easier to programme patients and then to have less side effects,” she said.
However, positioning of directional leads has been more challenging than the conventional DBS leads, and current studies will determine the extent of its effectiveness.
Meanwhile, a study published by researchers at University of California, San Francisco and The Ohio State University in 2021, studied how gene therapy could address a deficiency of aromatic L-amino acid decarboxylase (AADC) – a rare genetic disorder characterized by insufficient synthesis of dopamine and serotonin.
The trial, which investigated the safety and efficacy of viral vector expressing AADC, showed that participants – seven children – who underwent the therapy had an increased dopamine metabolism, and oculogyric crises – a condition characterized by spasmodic movements of the eyeballs, and is sometimes expressed in Parkinson’s disease and parkinsonism – was resolved. Thereby, gene delivery for AADC deficiency was gathered to be efficacious in enhancing motor functions, indicating its potential for treating Parkinson’s.
New research finds link between the gut microbiome and Parkinson’s disease
A study by the University of Alabama in the U.S. has found a link between the gut microbiome and the development of Parkinson’s disease. The research, led by Haydeh Payami, professor in the Department of Neurology at the university, examined 257 species of organisms in the microbiome, and it was concluded that 30% of them were associated with Parkinson’s disease.
“We found evidence for multiple mechanisms that we know are linked to PD, but we didn’t know they were happening in the gut also, and are orchestrated by the microbiome,” said Payami.
A spectrum of variations was observed. The number of bacteria like Bifidobacterium dentium, Actinomyces oris and Streptococcus mutans was six times more in individuals with Parkinson’s, while ones like Blautia wexlerae and Roseburia intestinalis were distinctly reduced.
Although a relationship between neurodegenerative disorders and the gastrointestinal system has previously been proven, this study gives a wider outlook on Parkinson’s, with regard to how it is affected by the gut microbiome.
“This is exciting research, as metagenomics is a new, albeit fast-evolving field, and the resources, methods and tools, while state-of-the-art, are still in development,” said Payami, who expressed that in the future, more tools could help delve into the origins of Parkinson’s disease, and potentially attempt to manipulate the microbiome to prevent its progression.
AbbVie’s candidate hits wall but could it be a blockbuster drug?
As levodopa remains a forerunner in Parkinson’s treatment, U.S. based pharmaceutical Abbvie’s drug candidate ABBV-951, composed of carbidopa and levodopa prodrugs, has generated buzz for its potential ability to treat motor fluctuations in patients with advanced Parkinson’s disease.
Although the drug received a Complete Response Letter (CRL) in March 2023, from the U.S. Food and Drug Administration (FDA) for the New Drug Application (NDA), indicating that the FDA has not approved the candidate yet, ABBV-951 showed significant improvement in clinical trials when compared to other levodopa drugs, without patients experiencing troubled dyskinesia.
As the candidate ABBV-951 is designed to provide a 24-hour, continuous subcutaneous delivery of carbidopa and levodopa to replace dopamine in the brain, the drug would be used to treat patients with high unmet need.
While the biopharma plans to resubmit its application soon, the candidate’s dosing flexibility has been praised, and ABBV-951 “could be an alternative for patients ineligible for DBS” or for those who do not want to undergo surgery, according to the Drugs to Watch 2023 report by analytics company Clarivate.
Landmark NADPARK trial shows improved NAD metabolism in individuals with Parkinson’s
Recent research by Haukeland University Hospital led by Charalampos Tzoulis, professor at the University of Bergen, has shown that the oral intake of nicotinamide riboside (NR) enhances NAD-metabolism in individuals with Parkinson’s disease, and offers encouraging insight into its therapeutic potential.
Titled the NADPARK study, the trial was conducted to establish whether the metabolism of NAD – a metabolite responsible for maintaining cellular stability which is deficient in Parkinson’s patients – can be boosted in the brain of people with Parkinson’s disease, by ingesting NR, which is an NAD-precursor.
“We believe that augmenting the brain’s NAD metabolism targets and rectifies multiple disease-related processes specific to Parkinson’s disease, such as mitochondrial dysfunction, DNA-damage, epigenetic dysregulation, and neuroinflammation. In addition, we postulate that NAD-replenishment may also optimize neuronal metabolism and fortify neurons, thereby rendering them more resilient against age-related stress and neurodegenerative diseases,” said Tzoulis.
Tzoulis expressed that the results are “highly encouraging” adding that it nominates NR as a “potential neuroprotective therapy for Parkinson’s disease, warranting further investigation in larger trials.”
To further understand the extent of NAD replenishment therapy to modulate the progression of Parkinson’s disease, an ongoing follow-up phase II NOPARK study is being conducted. According to Tzoulis, if the trial is successful, it would be a step towards the development of a regulated drug for the indication of Parkinson’s disease.
“There are currently no treatments able to delay or arrest the progression of Parkinson’s disease. Thus, affected persons face a future of progressive disability and early death. If NAD-replenishment proves to have neuroprotective, disease-modifying action in Parkinson’s disease, this would revolutionize the field, offering for the first time, hope for an improved prognosis and perhaps, even a cure,” said Tzoulis.
“The impact of such a therapy would be profound for patients, science, and society as a whole.”
New technologies related to Parkinson’s disease
- Treatment for Neurodegenerative Diseases such as Alzheimer’s – Rosalind Franklin University
- Peptide Therapeutic for Parkinson’s Disease – University of Toronto
- Midbrain‐Microglia Assembloids – University of Luxembourg
- Neuronal Activity Imaging System – Western University
- New Peptide Drug for the Treatment of Alzheimer’s Disease – Okinawa Institute of Science and Technology (OIST)