Five Breakthrough Directions in Parkinson's Disease Therapeutics: From Focused Ultrasound to NAD+ Metabolism Modulation

Parkinson’s disease is named after the British surgeon James Parkinson. His most famous work, *An Essay on the Shaking Palsy*, is a clinical account of a debilitating condition that causes movement disorders. Parkinson’s disease was first described as a neurological syndrome in 1817. However, symptoms resembling those of Parkinson’s disease were documented as early as 1000 BC in ancient Indian texts and Chinese records.

Jean-Martin Charcot, the French neurologist who named the disease, concluded that Parkinson’s disease is distinct from other tremor disorders, particularly multiple sclerosis, because he observed that not all patients with Parkinson’s disease exhibit tremor symptoms.

Clinically, therapeutic intervention should be initiated upon a confirmed diagnosis of Parkinson’s disease. One commonly used medication is hyoscyamine, a plant-derived alkaloid with sedative properties. As an anticholinergic agent, it inhibits the action of the neurotransmitter acetylcholine in the central nervous system (CNS) and is employed to control tremors and alleviate muscle rigidity.

Subsequently, in the 20th century, with the advent of the breakthrough drug levodopa, dopamine-based therapies began to garner attention. As a temporary substitute for dopamine (levels of which decline in patients with Parkinson’s disease), levodopa can alleviate motor impairments caused by the disease. However, the side effects of this medication have also drawn concern; in addition to known symptoms such as nausea and dizziness, long-term use may induce dyskinesia.

Over the years, as deep brain stimulation has garnered increasing attention in therapeutic research, surgical intervention has also become a viable treatment option for Parkinson’s disease.

However, Parkinson’s disease affects approximately 10 million people worldwide, and its prevalence is projected to double over the next two decades. The current need for effective treatments remains unmet, prompting researchers to strive for solutions.

In recent therapeutic research, the following five advances in Parkinson’s disease studies may bring transformative changes to treatment research.

Focused ultrasound technology is emerging as a highly sought-after innovation, with recent advancements drawing significant attention from the industry. Notably, researchers at the University of North Carolina at Chapel Hill School of Medicine (UNC) led a clinical trial demonstrating that focused ultrasound can improve motor disorders in patients with Parkinson’s disease.

This therapy aims to address involuntary movements that may occur in patients with Parkinson’s disease. These involuntary movements include twitching, jerking, twisting, or writhing of the face, arms, legs, or trunk, and typically appear in Parkinson’s disease patients who have been taking levodopa for an extended period. Levodopa is an oral therapeutic agent that increases dopamine levels in the brain and alleviates the symptoms of the condition.

In the trial, researchers from the University of North Carolina at Chapel Hill School of Medicine (UNC) evaluated 94 patients with Parkinson’s disease and found that 75% of those who underwent focused ultrasound therapy maintained positive therapeutic effects approximately one year after treatment completion. In addition to improving motor function and reducing involuntary movements, this therapy eliminates surgical risks, as the procedure requires no incisions.

Prior to this, surgical procedures commonly performed for patients with Parkinson’s disease included thalamotomy and pallidotomy. These procedures cause lesions in the patient’s thalamus or globus pallidus regions, particularly benefiting those experiencing tremors—an involuntary movement affecting 80% of Parkinson’s patients. Julie Pilitsis, a functional neurosurgery specialist at the Marcus Neuroscience Institute in Florida, noted that these surgeries involve creating an incision in the thalamus, thereby causing brain damage; in contrast, methods such as focused ultrasound are becoming increasingly attractive.

“Focused ultrasound technology does not involve implanting anything into the brain; instead, it only requires the use of a magnetic resonance imaging (MRI) scanner... meaning that patients no longer need to undergo craniotomy,” said Julie Pilitsis. “I fully understand why older patients are reluctant to undergo surgery.”

In 1997, deep brain stimulation (DBS) began to be used for the treatment of Parkinson’s disease tremor. The procedure was approved in 2002 for treating advanced-stage symptoms of Parkinson’s disease and received further approval in 2016 for earlier-stage symptoms, targeting patients whose motor symptoms are fully managed with medication. Recently, DBS has garnered widespread attention due to its combination with stem cell therapy and gene therapy for Parkinson’s disease.

Some studies have even considered combining gene therapy with DBS to supplement dopamine levels in the brain.

According to Julie Pilitsis, stem cell therapy and gene therapy appear promising for the treatment of Parkinson’s disease in the future.

“The technologies we currently see include only electrical currents or ultrasound, among others. But over time, these tools will become increasingly advanced,” said Julie Pilitsis.

DBS works similarly to a pacemaker, stimulating specific areas of the brain through implanted electrodes.

Julie Pilitsis explained the importance of directional leads, which are designed to expand the capabilities of DBS by inducing stimulation with greater precision. “This is really very helpful, as it makes programming easier for patients and reduces side effects,” she said.

However, compared with traditional DBS leads, the positioning of directional leads is more challenging. Julie Pilitsis’s current research will evaluate the extent of their efficacy.

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

This trial investigated the safety and efficacy of an AADC-expressing viral vector. The results showed increased polyamine metabolism in seven pediatric participants who received the therapy, along with alleviation of oculogyric crises (a condition characterized by spasmodic eye movements, sometimes observed in Parkinson’s disease and parkinsonism). Therefore, gene vector delivery for AADC deficiency is considered effective in enhancing motor function, indicating its potential for treating Parkinson’s disease.

A study conducted by the University of Alabama has identified a link between gut microbiota and the pathogenesis of Parkinson’s disease. Led by Professor Haydeh Payami from the Department of Neurology, the study examined 257 microbial species and concluded that 30% of the gut microbiota are associated with Parkinson’s disease.

“We have identified multiple mechanisms associated with Parkinson’s disease, but we do not know how they occur in the gut or which microbial species are involved,” said Payami.

Researchers have also observed a series of changes in related studies: In the gut microbiota of patients with Parkinson’s disease, the abundance of bacteria such as Bifidobacterium-like species, Actinomyces naeslundii, and Streptococcus mutans increased sixfold, while Clostridium wexlerae and Rhodoglobus intestinalis were significantly reduced.

Although the relationship between neurodegenerative diseases and the gastrointestinal system has been previously established, this study provides a broader perspective on how the gut microbiota influences Parkinson’s disease.

“This is exciting research because microbiomics is an emerging yet rapidly evolving field; although its resources, methods, and tools are state-of-the-art, it is still under development,” Payami stated. In the future, more tools will be available to help investigate the origins of Parkinson’s disease and to attempt modulating the gut microbiota to halt disease progression.

ABBV-951, a candidate drug from the US pharmaceutical company AbbVie, is composed of carbidopa and a levodopa prodrug, and has generated significant excitement due to its potential in treating motor fluctuations in patients with advanced Parkinson’s disease.

In March 2023, the drug received a Complete Response Letter (CRL) from the U.S. Food and Drug Administration (FDA) regarding its New Drug Application (NDA). Although the FDA has not yet approved this candidate drug, ABBV-951 demonstrated significant efficacy in clinical trials compared with other levodopa-based therapies, and patients did not experience dyskinesia that interferes with daily functioning.

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

AbbVie plans to resubmit its application soon, and the dosing flexibility of this candidate drug has also been well received by the industry. In its “Drugs to Watch in 2023” report, the analytics firm Clarivate noted that ABBV-951 “could become an alternative for patients who are not eligible for or do not wish to undergo DBS surgery.”

A recent study led by Charalampos Tzoulis, a professor at the University of Bergen, demonstrates that oral nicotinamide riboside (NR) can enhance NAD metabolism in patients with Parkinson’s disease. This experiment provides encouraging evidence for the use of NR in the treatment of Parkinson’s disease.

The study, named NADPARK, aims to determine whether the intake of NR (a NAD precursor) can enhance NAD metabolism in the brains of patients with Parkinson's disease. NAD is a metabolic substance responsible for maintaining cellular stability, and it is typically deficient in patients with Parkinson's disease.

“We believe that enhancing NAD metabolism in the brain can improve multiple symptoms characteristic of Parkinson’s disease, such as mitochondrial dysfunction, DNA damage, epigenetic abnormalities, and neuroinflammation. Furthermore, we hypothesize that NAD supplementation can optimize neuronal metabolism and strengthen neurons, thereby increasing their resistance to age-related stress and neurodegenerative diseases,” said Tzoulis.

Tzoulis described the results as “highly encouraging,” noting that NR is a “potential neuroprotective therapy for Parkinson’s disease, warranting further investigation in larger-scale trials.”

To further elucidate the extent to which NAD supplementation therapy modulates Parkinson’s disease progression, NOPARK is currently conducting a Phase II clinical trial. Tzoulis stated that if the trial proves successful, it would represent a step toward the development of regulated pharmaceutical agents for the treatment of Parkinson’s disease.

“There are currently no treatments capable of slowing or halting the progression of Parkinson’s disease. Consequently, patients face a fate of progressive disability and premature death. If NAD supplementation is proven to exert neuroprotective and disease-modifying effects in Parkinson’s disease, it would spark a revolutionary change in the field, making improved prognosis—and even a cure—for Parkinson’s disease possible for the first time,” said Tzoulis.

“This is of great significance to patients, the scientific community, and society as a whole.”

Source: https://www.labiotech.eu/best-biotech/parkinsons-disease-research-advancements/