Findings published recently in Nature Medicine have demonstrated the ability of an experimental drug, developed by researchers at Johns Hopkins University School of Medicine (MD, USA), to halt Parkinson’s disease progression. The compound is reported to block the hallmark degeneration of brain cells in cultures of human brain tissue and in mouse models, and is expected to move into clinical trials this year.
If the planned clinical trials for the experimental therapeutic are successful in humans, this could be one of the first treatments to specifically target Parkinson’s disease progression, rather than the symptoms.
The compound, NLY01, binds glucagon-like peptide-1 receptors on the surface of cells. This is similar to available therapeutics used to treat Type II diabetes by increasing blood insulin levels. This class of drugs has long been thought to have neuroprotective effects, but research has never before been carried out.
NLY01 was tested on three of the brain’s major cell types: astrocytes, microglia and neurons. Microglia – a cell type that sends signals throughout the central nervous system in response to trauma – were found to have two times more binding sites for NLY01 than the other cell types in healthy cells, and ten times higher in cells associated with Parkinson’s disease.
Microglia cells are known to send signals that convert astrocytes into activated astrocytes – aggressive cells that degrade connections between cells in the brain, causing neuronal death.
"The activated astrocytes we focused on go into a revolt against the brain," commented senior author, Ted Dawson, professor of neurology at Johns Hopkins School of Medicine, "and this structural breakdown contributes to the dead zones of brain tissue found in those with Parkinson's disease. The ideas was that if we could find a way to calm those astrocytes, we might be able to slow the progression of Parkinson's disease."
Preliminary experiments highlighted the ability of NLY01 to turn off activating signals in healthy human-derived microglia. When the healthy astrocytes were combined with treated microglia, they did not convert into activated astrocytes, and it was suspected that NLY01 could protect neurons throughout the body in this manner.
The hypothesis was further evaluated by testing the novel drug in mouse models of Parkinson’s disease. NLY01 was found to protect against the development of Parkinson’s-like symptoms in mice injected with α-synuclein – the primary driver of Parkinson’s disease – and extended the lifespan of transgenic mice by more than 120 days.
Further investigations concluded that NLY01-treated mice exhibited few neurodegenerative symptoms associated with the onset of Parkinson’s disease.
The team hope to take the drug candidate through to clinical trials in order to test the safety and efficacy of the compound in humans, and expect to see few problems at this stage due to the existing safety profiles of similar drugs. Dawson concluded that he hoped NLY01 could, in a relatively short period of time, make an impact on the lives of those with Parkinson’s.
Yun SP, Kam TI, Panicker N et al. Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson’s disease. Nat. Med. doi:10.1038/s41591-018-0051-5 (2018); www.hopkinsmedicine.org/news/media/releases/experimental_drug_stops_parkinsons_disease_progression_in_mice?preview=true