Patients with moderately severe Parkinson’s Disease harbor significant defects in blood vessels that act as a gatekeeper between the body’s general circulation and the brain, scientists at Georgetown University Medical Center have discovered during a clinical trial testing the efficacy of the drug nilotinib in treating patients with Parkinson’s Disease. In 2007, the FDA approved nilotinib (brand name, Tasigna) for chronic myelogenous leukemia (CML).

The study is detailed in an article published in the journal Neurology Genetics on November 12, 2021, titled “CSF MicroRNAs Reveal Impairment of Angiogenesis and Autophagy in Parkinson Disease.” This longitudinal study (clinical trial number, NCT02954978) uses advanced genomics to monitor microRNAs in patients’ cerebrospinal fluid.

The researchers claim their finding suggests the blood brain barrier, which generally acts as a filter to protect the brain against toxins that have found their way into the systemic circulation but allows the passage of nourishing nutrients into the brain, doesn’t work optimally in some patients with Parkinson’s disease.

The study shows, in a subset of patients with moderately severe Parkinson’s Disease this critical vascular barrier prevents toxins from leaving the brain and inhibits essential nutrients such as glucose from entering it. The dysfunctional blood brain barrier also allows inflammatory cells and molecules to enter and damage the brain.

“To our knowledge, this is the first study to show that the body’s blood brain barrier potentially offers a target for the treatment for Parkinson’s disease,” said the study’s senior author, Charbel Moussa, MBBS, PhD, associate professor of neurology and director of the translational neurotherapeutics program at the Georgetown University Medical Center. “Knowing that a patient’s brain vascular system is playing a significant role in the progression of the disease is a very promising discovery.”

The unexpected finding was noted during Phase II of the clinical trial when next generation whole genome sequencing was used to analyze the cerebrospinal fluid of 75 Parkinson’s patients, before and after treatment with a placebo or nilotinib.

“The research protocol adopted an ‘adaptive’ design switching between placebo to low and high drug doses to delineate the effects of nilotinib in moderately severe Parkinson’s disease patients. This was necessary because all patients received optimal SOC and 30% deep brain stimulation and we knew that medical stabilization will not lead to meaningful clinical changes or decline in placebo for at least 12 months,” said Moussa.

Charbel Moussa, MBBS, PhD, associate professor of neurology and director of the translational neurotherapeutics program at the Georgetown University Medical Center is senior author of the paper

“To overcome these issues and learn whether you can use 75 patients to inform definitive larger trials, we treated patients for 27 months. [Our goal was] to better understand whether nilotinib can induce changes in miRNA and control of gene expression that affect biological pathways that will stabilize or improve Parkinson’s symptoms when the effects of other SOC treatments wane (>12months), suggesting a disease modifying effect. This was indeed a very highly successful strategy.”

The randomized, double-blinded initial trial followed patients for 27 months, that included a period of one year when the patients received either a placebo or nilotinib at a dose of 150mgs or 300mgs. The primary objective of the study was to investigate changes in microRNAs in the cerebrospinal fluid in individuals with moderately severe Parkinson’s Disease.

During the second part of the Phase II study all participants were randomized to another year-long course of either 150mgs or 300mgs of the drug, following a three-month drug washout period. All patients underwent lumbar puncture to collect cerebrospinal fluid at baseline, 12 months, and 27 months.

Analysis at 27 months showed that nilotinib was safe and patients who received nilotinib showed a dose-dependent increase in dopamine, the neurotransmitter decreased due to neuronal death in patients with Parkinson’s disease.

An earlier outcome of the study, published in Movement Disorders in March 2021, showed nilotinib was able to halt long-term motor and non-motor decline, including decline in cognition and quality of life. “It appeared nilotinib halted motor and non-motor decline in the patients taking the 300mgs higher dose,” said Moussa. The current study that conducted a systematic epigenomic analysis of the global state of gene expression may help explain the clinical outcomes reported earlier.

Nilotinib inactivated a protein called discoidin domain receptor or DDR1 that was compromising the function of the blood brain barrier. When DDR1 was inhibited, transport across the blood brain barrier was normalized, and inflammation in the brain declined to a point where dopamine synthesis increased.

“You can [now] go to the top of the echelon–brain mircoRNAs that control global gene expression–to determine how a drug like nilotinib alters major biological pathways to prevent pathology and produce a positive clinical effect. In Parkinson’s patients, nilotinib repairs brain vascular tissues, which results in statistically significant, clinically meaningful outcomes,” Moussa said.

The analysis of the miRNA data showed changes in genetic pathways that regulate collagen, the extracellular matrix, the growth of blood vessels and autophagy-lysosome pathways over 12 months in patients with moderately severe Parkinson’s disease, suggesting these pathways play a role in the progression of the disease.

“Not only does nilotinib flip on the brain’s garbage disposal system to eliminate bad toxic proteins, but it appears to also repair the blood brain barrier to allow this toxic waste to leave the brain and to allow nutrients in,” Moussa said. “Parkinson’s disease is generally believed to involve mitochondrial or energy deficits that can be caused by environmental toxins or by toxic protein accumulation. It has never been identified as a vascular disease.”

Bolstered by the data from the phase II trials, the team is planning a larger multicenter phase III trial to establish the superiority of nilotinib over current treatment options in patients with Parkinson’s Disease.

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