Parkinsons disease is a progressive neurological disorder affecting approximately one million people in the United States, characterized by tremors, muscle rigidity, impaired movement, fatigue, and eventually dementia. Most patients begin showing symptoms in their 60s, though cases have been reported in patients as young as two years old. Despite decades of research, available treatments address symptoms only, with no approved therapy capable of slowing the underlying neurodegeneration. Researchers at Johns Hopkins University have now developed an experimental drug called NLY01 that, in both human brain cell cultures and mouse models, blocked the degradation of brain cells that defines Parkinsons disease, and extended survival in transgenic mice by more than 120 days.
How NLY01 Targets Parkinsons Disease at the Cellular Level
NLY01 belongs to a class of compounds that bind to glucagon like peptide 1 receptors, the same type of receptor targeted by several drugs widely used to treat type 2 diabetes, including exenatide, liraglutide, and dulaglutide. While earlier animal studies had suggested neuroprotective potential for this drug class, the precise mechanism by which it acted in the brain had not been established. The Johns Hopkins team set out to determine exactly which brain cells NLY01 was affecting and how.
Testing NLY01 on three major brain cell types, including astrocytes, microglia, and neurons, the researchers found that microglia had the highest concentration of binding sites for the drug, approximately twice as many as the other cell types, and ten times higher in humans with Parkinsons disease compared to those without it. This concentration pointed directly to microglia as the primary target.
The Role of Microglia and Astrocytes in Parkinsons Disease Progression
Microglia are brain cells that respond to infection or injury by sending chemical signals throughout the central nervous system. The Johns Hopkins team had previously established that these signals can convert astrocytes, the star shaped cells that support neuronal communication, into an aggressive activated state. Once activated, these astrocytes attack the connections between brain cells, causing neurons to die off and producing the dead zones of brain tissue characteristic of Parkinsons disease.
When the researchers treated human microglia with NLY01 in laboratory grown cell cultures, they found the drug effectively switched off the activating signals. Healthy astrocytes combined with NLY01 treated microglia did not convert into the destructive activated form and remained functional neuroprotective cells. This suggested that NLY01 could interrupt the cellular cascade that drives neurodegeneration in Parkinsons disease before it begins.
Parkinsons Disease Mouse Model Results for NLY01
The team tested NLY01 in two separate mouse models of Parkinsons disease. In the first, mice were injected with alpha synuclein, the protein known as the primary molecular driver of Parkinsons disease. Untreated mice showed pronounced motor impairment over six months in behavioral tests. Mice treated with NLY01 maintained normal physical function and showed no loss of dopamine neurons, the cell population whose destruction is the defining feature of Parkinsons disease.
In the second experiment, transgenic mice genetically engineered to overproduce human type alpha synuclein were used to model familial Parkinsons disease. Under normal conditions these mice succumb to the disease within 387 days. Treatment with NLY01 extended survival by more than 120 days, and examination of the treated mice’s brains showed few signs of the neurodegenerative characteristics typical of Parkinsons disease.
What Comes Next for NLY01 and Parkinsons Disease Clinical Trials
Lead investigator Ted Dawson, MD, PhD, director of the Institute for Cell Engineering at Johns Hopkins, described NLY01 as amazingly protective of target nerve cells and expressed confidence that the drug could make a meaningful impact on patients in a relatively short period of time if clinical trials proceed as hoped. The drug was expected to move into clinical trials following publication of the study in Nature Medicine.
NLY01 is a long acting formulation with improved brain penetration compared to the FDA approved diabetes drugs in its class. Dawson noted that based on the established safety profile of related compounds already in clinical use, he does not anticipate major obstacles to testing NLY01 in humans. If successful, it could become one of the first treatments to directly target the progression of Parkinsons disease rather than managing its symptoms.
To read more about neurology and CNS research, visit the FOMAT blog. FOMAT conducts Parkinsons disease and neurology clinical trials at sites across the United States. To learn more about active studies, visit FOMAT’s patient studies page.
For the full source, see the original article at DDDmag.com.