While Parkinson’s disease was first characterized 200 years ago, significant progress in unraveling the causes of the neurodegenerative syndrome has occurred only this century. This has accelerated drug development to the point where experts say new therapies to prevent or slow disease progression are now within sight.  

“In the past two decades, the field has built an appreciation for the role of genetics and its interplay with environmental and lifestyle factors to determine Parkinson’s risk,” says Todd Sherer, Ph.D., president and CEO of The Michael J. Fox Foundation for Parkinson’s Research (MJFF). “In most cases, genetic predisposition and an environmental trigger lead to Parkinson’s.”

The renewed excitement surrounding Parkinson’s research involves recent scientific breakthroughs that have led to clinical trials of therapies targeting specific genetic elements of the disease “with potential to slow or stop disease progression,” Sherer explains.

Gerald Commissiong, president and CEO of Amarantus Biosciences – which is developing a neurotrophic factor to treat Parkinson’s – believes “a functional cure for patients is within reach, adding, “I think the potential technologies that could lead to major advancements are already available, and it will be a matter of understanding how well they can work together to lead to disease modification.”

Milton Werner, CEO and founder of Inhibikase, agrees. “As a company, we believe that a cure is possible, likely using a combination therapy strategy,” he says. Inhibikase is developing a small molecule kinase inhibitor to disrupt development and progression of the disease.

For Gene Kinney, president and CEO of Prothena, “This is an exciting time for neuroscience research, and I am extremely optimistic about the prospect of new and better treatments emerging in the near future.” Prothena is developing a monoclonal antibody targeting a specific protein believed to be involved in Parkinson’s.

Parkinson’s is second only to Alzheimer’s disease in prevalence of neurodegenerative disorders, according to ParkinsonsDisease.net. MJFF says nearly 1 million people in the US are living with the disease, which is estimated to cost the country $26 billion a year.

An urgency for new Parkinson’s disease therapies is underscored in a January 2018 Journal of the American Medical Association Neurology report, which describes the spread of Parkinson’s as a pandemic. According to the report, “Neurological disorders are now the leading cause of disability in the world. The fastest growing is Parkinson’s, whose growth is surpassing that of Alzheimer’s disease.”

Meanwhile, the number of people worldwide living with Parkinson’s is expected to double from nearly 7 million in 2015 to more than 14 million by 2040, the report states.

In this installment of WuXi’s new communications platform on the future of drug discovery and development, leading experts in Parkinson’s disease discuss the complexity of the condition, the challenges facing researchers and the latest advances in drug development. They include Gerald Commissiong, Gene Kinney, Todd Sherer, and Milton Werner. Their complete interviews are also are available on this website.

The U.S. National Institutes of Neurological Disorders and Stroke (NINDS) defines Parkinson’s disease as “a degenerative disorder of the central nervous system that belongs to a group of conditions called movement disorders,” caused by the loss of brain cells that produce dopamine.

The disease affects 50 percent more men than women and the average age of onset is 60 when symptoms such as tremors, rigidity, bradykinesia and impaired balance usually begin to emerge.

Although the “actual cause of the cell loss death” is not known, NINDS notes that genetic mutations, such as those involving the alpha-synuclein gene, have been linked to the disease as well as environmental factors, such as exposure to toxins, and damage to the mitochondria, which are energy-producing organelles inside cells.

The main drug therapy for Parkinson’s remains levodopa – developed in the 1960s – and is used in combination with other drugs to enable brain cells to make dopamine. However, the drugs only address a subset of symptoms and do not halt progression of the disease.

Development of new drugs focused on both symptoms and causes have increased dramatically since the completion of the Human Genome Project in 2000.

“Parkinson’s research has undergone a genetics revolution in the past 20 years, opening doors to new understanding of risk, onset and progression and pointing to therapeutic targets and biomarker candidates now doggedly pursued by scientists,” says The Michael J. Fox Foundation’s Todd Sherer.

Amarantus Biosciences Gerald Commissiong adds, “It is often said that genetics loads the gun with the environment pulling the trigger. It certainly seems this likely holds true in Parkinson’s.”

Inhibikase’s Milton Werner agrees environmental factors “likely do contribute to development of Parkinson’s.” But he says, “I think it’s still a mystery.” More significant, he adds, is research suggesting “the development of Parkinson’s arises from damage caused by aggregated or misfolding alpha-synuclein that accumulates in affected regions of the brain.”

Another consequence of the genetics research into Parkinson’s is a greater understanding of its complexity and multi-dimensional nature.

“Parkinson’s is no longer believed to be a disease affecting only areas of the brain that mediate movement, but instead is a whole-body disease that affects movement as well as a number of other functions,” Prothena’s Gene Kinney says.

Meanwhile, Sherer observes, “We are also finding genetics similarities between Parkinson’s and non-brain diseases such as Gaucher and Crohn’s that could help us to better understand and treat across conditions.”

Where are we now?

No medicines that cure or slow the progression of Parkinson’s have yet reached patients. NINDS defines three categories of existing drug therapies – those that increase the level of dopamine, mimic dopamine or slow the breakdown of the neurotransmitter; drugs that target other neurotransmitters to ease symptoms of the disease; and drugs that treat non-motor symptoms, such as depression.

“Neurodegenerative diseases such as Parkinson’s and Alzheimer’s remain areas of some of the highest unmet need in medicine,” Kinney says. “Currently available medicines are somewhat effective in treating the symptoms, but become less useful as the underlying disease progresses.”

However, recent advances in understanding the genetics of neuroscience have improved the hunt for a cure, Kinney adds, by revealing “more about the factors that cause the dopamine-producing cells in the brain to die, including alpha-synuclein. In patients with Parkinson’s, aggregated alpha-synuclein forms clumps called Lewy bodies that are a hallmark of the disease.”

Prothena has developed a monoclonal antibody, called PRX002/RG7935, targeting alpha-synuclein. The drug candidate “is designed to preferentially target aggregated alpha-synuclein to clear it, prevent new aggregates from forming, prevent transmission from one neuron to the next and slow or reduce neurodegeneration,” Kinney says.

Inhibikase is also focused on alpha-synuclein. Werner explains that biochemical pathways involved in Parkinson’s transport misfolded or aggregated alpha-synuclein “into the affected neurons through the LAG-3 (Lymphocyte-activation gene 3) and related receptors which, once inside the cell, triggers a biochemical cascade that has two effects: c-Abl kinase chemically modifies alpha-synuclein to create a toxic form that drives cell death…and is transported from one neuron to the next.”

Inhibikase, Werner says, is developing a small molecule “inhibitor of c-Abl as a disease modifying therapy for Parkinson’s.”

Amarantus, on the other hand, is taking a regenerative medicine approach, focusing on the mesencephalic astrocyte-derived neurotrophic factor (MANF). Commissiong observes, “MANF is an endoplasmic reticulum stress response protein that has very specific activity in regenerating dopaminergic neurons leading to cellular recovery, synaptogenesis and normalization of dopamine levels in animal models of Parkinson’s disease.”

Commissiong explains that Amarantus plans to deliver MANF “into the substantia nigra and striatum in the brain’s basal ganglia network…to regenerate the utility of the dying dopaminergic neurons.”

Other genetic targets, Sherer says, include the glucosylceramidase beta gene (GBA) and the leucine rich repeat kinase 2 gene (LRRK2). While the alpha-synuclein protein is believed to be involved in both familial and the more common sporadic forms of Parkinson’s, mutations in the GBA and LRRK2 genes are linked to about 10% of cases.

Advances in understanding the genetics of Parkinson’s enable development of a “precision medicine” approach to battling the complex disease, Sherer adds. “This strategy of directing treatments based on biology and etiology, rather than solely on clinical presentation, will hopefully yield success in our efforts to slow and stop disease progression.”

MJFF, which Sherer describes as “the world’s largest non-profit funder of Parkinson’s disease research,” has invested $800 million since the organization’s founding in 2000. It supports clinical development of new drugs aimed at disease modification as well as motor and non-motor symptoms.

“In addition to granting funds, we build infrastructure and provide resources to help scientists accelerate their projects,” Sherer says. “Our foundation has developed and characterized an extensive catalog of research tools such as assays, antibodies and models, which are available quickly and at cost to researchers in academia and industry.”

Where are we headed?

The experts interviewed for this white paper agree that drugs to stop or slow progression of Parkinson’s likely will be available sooner rather than later, but they also acknowledge that challenges remain.

“The greatest medical benefit in considering treatments with the ability to favorably alter the course of Parkinson’s disease would be to treat patients at the earliest stage while symptoms remain mild and manageable or prevent the disease entirely,” Kinney says. To achieve those goals, he says, “The single most important breakthrough would be the ability to identify patients at risk or in the earliest stages of their disease when changes in the brain are occurring, but before there are clinical symptoms.”

Sherer also observes, “Parkinson’s clinical and biological variability has challenged drug development. We need objective, selective biomarker tests to predict, diagnose and monitor Parkinson’s disease and test the impact of therapeutic interventions.”

To help identify these biomarkers, Sherer says the MJFF sponsors the Parkinson’s Progression Markers Initiative, which is a large-scale study building a repository of data and biological samples collected from varied cohorts for analysis of the disease’s causes and progression.

According to Werner, “The most important needs are not so much biochemical breakthroughs, but understanding how the disease starts and identifying a sensitive marker for early disease recognition before damage is done.”

Another major challenge is the design of clinical trials. Patients enrolled in studies, Commissiong explains, are in the later stages of the disease and are the least likely to respond because they “have suffered loss of virtually all of their dopaminergic neurons. This is one of the things we have to work on in the design of clinical studies where we start to treat patients with experimental regenerative therapies earlier in the disease process.”

Despite these challenges, Sherer says trials are underway to test therapies against Parkinson’s genetic targets such as alpha-synuclein, GBA and LRRK2 with the potential to slow or stop disease progression. “While we still have much to learn about the safety and efficacy of these therapies, we could make significant strides in their development over the next five years,” he predicts.

Werner also agrees on a similar timeline for a significant breakthrough. “I think that within five to six years,” he says, “Parkinson’s will cease to be a devastating disease of progressive deterioration and transformed into one of halted progression that trends toward an eventual cure.”

Kinney adds that advances contributing to new Parkinson’s disease treatments are reflected in progress being made in other neurodegenerative disorders.

“Armed with better understanding of disease pathophysiology, new tools for imaging the brain, decoding DNA and evaluating and monitoring symptoms,” he says, “I believe we will see tremendous improvements in quality of life for patients with Parkinson’s and other neurodegenerative conditions. As our understanding continues to evolve, I fully anticipate that one day, the scientific and medical communities will be able to effectively identify and stop these types of diseases even before symptoms emerge.”