Five recent advances in Parkinson’s disease research

Named after the English surgeon James Parkinson, best known for his book ‘An Essay on the Shaking Palsy’ – a clinical report on a paralytic condition that causes motor impairment – ​​Parkinson’s disease was first described as a neurological syndrome in 1817. However, ancient Indian texts and sources -Chinese sources also record what appears to be a description of Parkinson’s disease, in 1000 BC.

Its difference from other tremor disorders, particularly multiple sclerosis, came after the French neurologist Jean-Martin Charcot, who also gave the disease its name, concluded that not all individuals with Parkinson’s disease develop tremors.

The researchers were also able to differentiate between Parkinson’s disease and Parkinsonism – an umbrella term used for a neurological disorder similar to Parkinson’s, often characterized by tremors, slow movements and stiffness.

As soon as the diagnosis was made, therapeutic interventions began, 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) – used to control tremors and reduce muscle stiffness.

Later, in the 20th century, dopamine-based therapies began to gain popularity, with Parkinson’s breakthrough drug levodopa gaining attention. As a temporary replacement for dopamine – a neurotransmitter that is decreased in Parkinson’s – levodopa relieves the motor symptoms caused by the disorder. However, side effects of the drug such as nausea and dizziness have been noted, and long-term use has caused motor problems in some patients.

Over the years, surgery has become a viable option as well, with deep brain stimulation gaining traction in therapeutic studies.

However, because this disease affects an estimated 10 million people worldwide, with prevalence expected to double in the next 20 years, there is an unmet need for therapeutic measures; what researchers are working on to achieve it.

As we observe Parkinson’s Awareness Month in April, here are five advances that could revolutionize therapeutic study.

Focused ultrasound: a new therapy for Parkinson’s with essential tremor

The novelty of focused ultrasound hasn’t faded away; in fact, the fast-developing technology has been making headlines lately after researchers at the University in Chapel Hill (UNC) School of Medicine led a clinical trial to show that the treatment improved motor impairment in people with Parkinson’s disease, a study was published. in February 2023.

This therapy also aims to treat dyskinesia, which is an involuntary movement – ​​twitching, jerking, twisting or writhing – of the face, arms, legs or trunk, observed in some patients with Parkinson’s disease who have been taking oral levodopa – which increases blood levels dopamine in the brain and relieve some of the symptoms of the disease – for a long time.

A trial conducted by the UNC, which assessed 94 Parkinson’s disease patients, saw that 75% of those who underwent focused ultrasound treatment maintained positive results for about a year after the treatment was finished. In addition to the patient achieving improved motor function and decreased dyskinesia, this treatment also eliminates the risks associated with surgery, as the procedure is non-incisional.

Previously, surgical procedures such as thalamotomy and pallidotomy, in which lesions are created in the thalamus or pallidum area of ​​the brain, especially for patients experiencing tremors – a symptom resulting in involuntary vibrating movements that affect 80% of people with Parkinson’s – were recommended. However, because the procedure aims to cut a hole in the thalamus, thereby damaging parts of the brain, methods such as focused ultrasound are becoming more attractive, according to Julie Pilitsis, a neurosurgeon at the Marcus Neuroscience Institute in Florida, who specializes in functional neurosurgery.

“Instead of putting something in the brain, you go to an MRI…Because now, you don’t have to have open brain surgery for this,” Pilitsis said.

“It’s really exciting for people – when they’re older, they don’t want to do surgery, and I totally get that.”

Deep brain stimulation and gene therapy for Parkinson’s are making headway

Having been around since 1997 to treat Parkinson’s tremor, deep brain stimulation (DBS) was approved in 2002 to treat symptoms of advanced Parkinson’s disease and again in 2016, to treat the early stages of the condition, for individuals whose motor symptoms are entirely controlled with drugs medicine. Recently, DBS has received attention as a potential precursor for stem cell therapy and gene therapy for Parkinson’s disease.

Some studies are even considering the possibility of 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 look promising for Parkinson’s.

“I think that’s where we see a field where electricity or ultrasound is our tool right now. But we see those tools getting advanced over time,” he said.

Just like a pacemaker, DBS stimulates certain parts of the brain through implanted electrodes.

Pilitsis explained the importance of direction cues designed to extend DBS capabilities by more accurately inducing stimulation. “That’s really helpful because it’s easier to program patients and then it has fewer side effects,” he said.

However, positioning lead leads is more challenging than conventional DBS leads, and current studies will determine their effectiveness.

Meanwhile, a study published by researchers at the University of California, San Francisco and The Ohio State University in 2021, studied how gene therapy can address L-aromatic acid decarboxylase (AADC) deficiency – a rare genetic disorder characterized by the synthesis of which is insufficient. dopamine and serotonin.

The trial, which investigated the safety and efficacy of an AADC-expressing viral vector, showed that participants – seven children – who underwent therapy experienced increased dopamine metabolism, and oculogical crisis – a condition characterized by spasmodic movements of the eyeballs, and sometimes expressed. in Parkinson’s disease and parkinsonism – resolved. Thus, gene delivery for AADC deficiency is considered to be efficacious in improving motor function, indicating its potential to treat Parkinson’s.

New study finds a link between the gut microbiome and Parkinson’s disease

A study by the University of Alabama in the US 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 concluded that 30% of them were associated with Parkinson’s disease.

“We found evidence for several mechanisms that we knew were associated with PD, but we didn’t know they also occur in the gut, and are regulated by the microbiome,” Payami said.

A spectrum of variation is observed. Number of bacteria likes Bifidobacterium teeth, Actinomyces oris And Streptococcus mutans is six times more in individuals with Parkinson’s, while the like Blautia vexlera And Roseburian intestine clearly reduced.

Although a link between neurodegenerative disorders and the gastrointestinal system has been demonstrated before, this study provides a broader view of Parkinson’s, with respect to how it is affected by the gut microbiome.

“This is an exciting research, because metagenomics is a new field, although it is developing rapidly, and resources, methods and tools, although sophisticated, are still under development,” said Payami, who stated that in the future, more tools could help investigate disease origins, and potentially trying to manipulate the microbiome to prevent its development.

AbbVie candidate hits a wall, but could it be a blockbuster drug?

As levodopa remains the precursor in the treatment of Parkinson’s, US-based Abbvie pharmaceutical candidate drug, ABBV-951, consisting of the prodrugs carbidopa and levodopa, 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 US Food and Drug Administration (FDA) for New Drug Applications (NDA), indicating that the FDA had not approved the candidate, ABBV-951 showed significant results. improvement in clinical trials when compared with other levodopa drugs, without patients developing problematic dyskinesia.

Because the ABBV-951 candidate is designed to provide continuous 24-hour subcutaneous delivery of carbidopa and levodopa to replace dopamine in the brain, the drug will be used to treat patients with high unmet needs.

While biopharma plans to resubmit its application soon, the candidate’s dosing flexibility has been praised, and ABBV-951 “could be an alternative for patients who are not eligible for DBS” or for those who do not wish to undergo surgery, according to the Drugs to Watch 2023 report by the analytics company Clarivate.

The NADPARK Landmark trial demonstrated increased NAD metabolism in individuals with Parkinson’s

A recent study by the University Hospital Haukeland led by Charalampos Tzoulis, professor at the University of Bergen, has shown that oral nicotinamide riboside (NR) intake improves NAD metabolism in individuals with Parkinson’s disease, and offers encouraging insight into its therapeutic potential. .

Titled the NADPARK study, the experiment was conducted to determine whether the metabolism of NAD – the metabolite responsible for maintaining cellular stability lacking in Parkinson’s patients – could be increased in the brains of people with Parkinson’s disease, by ingesting NR, which is a NAD-precursor.

“We believe that augmenting brain NAD metabolic targets and ameliorating several disease-related processes specific to Parkinson’s disease, such as mitochondrial dysfunction, DNA damage, epigenetic dysregulation, and neuroinflammation. Moreover, we postulate that NAD replenishment may also optimize neural metabolism and fortify neurons, thereby making them more resistant to age-related stress and neurodegenerative diseases,” said Tzoulis.

Tzoulis stated that the results were “very encouraging” adding that it nominated NR as “a potential neuroprotective therapy for Parkinson’s disease, which requires further investigation in a larger trial.”

To better understand the extent to which NAD addition therapy modulates Parkinson’s disease progression, a follow-up phase II NOPARK study is underway. According to Tzoulis, if the trial is successful, it will be a step toward developing a regulated drug for indications of Parkinson’s disease.

“There are currently no treatments that can delay or stop the progression of Parkinson’s disease. Thus, affected persons face a future of progressive disability and premature death. If NAD replenishment is shown to have neuroprotective, disease-modifying actions in Parkinson’s disease, it will revolutionize the field, offering for the first time, hope for a better prognosis and possibly, even a cure,” said Tzoulis.

“The impact of such a therapy would be profound for patients, science and society as a whole.”