Impaired blood-brain barrier may underlie Parkinson’s disease progression

Reuters Health - 26/11/2021 - A defect in the blood-brain barrier (BBB) that reduces its ability to remove toxins and to allow nutrients such as glucose to enter the brain may be responsible for Parkinson's disease progression, researchers say.

Nilotinib, a drug approved to treat leukemia, may reverse the defect, they suggest.

"Phase 2 results using nilotinib in both Alzheimer's and Parkinson's disease showed an overwhelming outcome in repairing the BBB and enhancing cleaning of toxic materials such as amyloid and tau and reducing inflammation, which all can be beneficial for cognition, behavior and motor symptoms," Dr. Charbel Moussa of Georgetown University Medical Center in Washington, D.C., told Reuters Health by email.

A phase 3 trial in early Alzheimer's disease will launch in early 2022, he said, and other studies in movement disorders are in the planning stage.

As reported in Neurology Genetics, Dr. Moussa and colleagues assessed longitudinal changes in cerebral spinal fluid (CSF) microRNAs (miRNAs) in 75 patients with moderately severe Parkinson's disease after single random ascending doses of nilotinib, and longitudinal miRNA expression after 150 mg and 300 mg nilotinib daily versus placebo for one year. The analyses are the second part of a phase II trial that lasted 27 months.

The longitudinal analysis was undertaken when no differences in miRNA expression were observed cross-sectionally between the treatment groups and placebo after a single nilotinib dose. The study used an adaptive design and all participants underwent a 3-month drug washout period before re-randomization.

Over one year, significant changes in the expression of miRNAs that control genes and pathways that regulate angiogenesis, autophagy, and the (BBB) components, primarily collagen, were observed, suggesting impairment of these pathways in Parkinson's disease progression in these patients.

The DDR1 protein was specifically pinpointed as playing a role in BBB malfunctioning (nilotinib is a DDR1 inhibitor).

"Nilotinib, 300 mg, treatment for 1 year led to reduction of collagens and engagement of DDR1 miRNAs, suggesting changes of DDR1 activity," the authors noted. "Collectively, these data suggest that DDR1 inhibition via nilotinib reverses the miRNA expression that led to vascular impairment in the CNS."

The study also found that different miRNAs indicating activation of genes associated with autophagy flux and clearance and angiogenesis were significantly altered in the nilotinib 300 mg versus the 150 mg and placebo groups, and that these changes correlated with clinical outcomes, as indicated in changes in the Unified Parkinson's Disease Rating Scale II + III.

Dr. Moussa said, "From the current study, we determined that we can use epigenomics to determine drug effects on biomarkers in clinical trials. We detected the entire microRNA genome in the CSF, meaning that this is a highly stable biomarker that can be used to overcome the unavailability and variability of protein and messenger RNA assays, especially when changes in these microRNAs are validated against extensive preclinical studies."

Further, he said, the team found that "nilotinib is a drug that is safe and has a disease-modifying effect even starting at the gene-regulation level (microRNAs are gene regulators), to favorably alter biological pathways that can yield positive clinical outcomes."

Dr. James Beck, Chief Scientific Officer at the Parkinson's Foundation, commented in an email to Reuters Health, "I am not surprised that one year of medication can lead to changes in the expression of genes in the cell. However, I believe the interpretation of those changes is purely speculative at this point and would require further research to support the...conclusions reached by the authors."

"It is important to understand how the changes in the microRNAs observed here compare to controls," he said. "There is also a need for replication to see if these findings hold. In addition, functional evidence is needed to understand whether the differences observed are truly meaningful or simply represent subtle changes (due) to the long-term use of nilotinib."

"Regarding the purported impact of nilotinib on Parkinson's disease, an independent trial has been conducted to test the efficacy of nilotinib and has failed to replicate the authors' prior findings," Dr. Beck concluded.

Dr. Moussa is an inventor on several U.S. and international Georgetown University patents to use nilotinib and other tyrosine kinase inhibitors as a treatment for neurodegenerative diseases. Georgetown University has spun out the technology to a start‐up company (KeifeRX LLC), from which Dr. Moussa receives consulting fees and the University, Dr. Moussa and a coauthor receive equities.

SOURCE: https://bit.ly/3rd75kZ Neurology Genetics, online November 12, 2021.

By Marilynn Larkin



Posted on 26 November, 20217 December, 2021