NLY01 is neuroprotective in the murine model of Parkinson's disease

An experimental drug that slows the progression of Parkinson's disease itself – as well as its symptoms – in mice, was developed by Johns Hopkins researchers. In experiments with human brain cell cultures and live mouse models, they report that the drug has blocked the degradation of brain cells that is the hallmark of Parkinson's disease. is surprisingly protective of target nerve cells, "

said Ted Dawson, MD, Ph.D., director of the Institute of Cell Engineering and professor of neurology at Johns Hopkins University Sc Hool of the Dawson explained that if the clinical trials planned for the drug, named NLY01, were successful in humans, it could be one of the first treatments to directly target the progression of Parkinson's disease and not just muscle rigidity , spasmodic movements, fatigue, vertigo and dementia, and other symptoms of the disease

GLP1R Agonists

According to the researchers, NLY01 acts by binding to what are called peptide receptors Glucagon-like (GLP1R) type 1 on the surface of some cells Similar drugs, called GLP1R agonists, are widely used in the treatment of type 2 diabetes to increase insulin levels in the body.

Although previous studies have suggested the neuroprotective potential of this class of drugs, researchers operated in the brain. To find out, Dawson and his team tested NLY01 on three major cell types of the human brain: astrocytes, microglia and neurons

They found that microglia, a type of brain cell that sends signals into the central nervous system in response to the infection. or injury, had the most sites for NLY01 to bind to – twice as high as other cell types, and 10 times higher in humans with Parkinson's disease compared to humans without the disease.

Dawson and his team knew that microglia secrete signals that converted astrocytes – the star-shaped cells that help neurons communicate with their neighbors – to aggressive "activated" astrocytes, which gnaw the connections between cells of the brain, causing the death of neurons. They speculated that NLY01 could stop this conversion.

"The activated astrocytes we have been focusing on are going into a revolt against the brain, and this structural degradation is contributing to the dead areas of brain tissue found in people with Parkinson's disease." The ideas were that if we could find a way to calm these astrocytes, we may be able to slow the progression of Parkinson's disease, "

said Dawson.

Blocking Astrocyte Conversion

In a Preliminary Laboratory Experiment- The Dawson team treated human microglia with NLY01 and found that they were able to turn off activating signals.

When healthy astrocytes were combined with treated microglia, they did not transform into destructive astrocytes and remained neuroprotective cells. The Dawson team suspected that neurons throughout the body could be protected in the same way.

They explored this hypothesis by testing the efficacy of the drug in mice designed to have a rodent version of Parkinson's disease. mice with alpha-synuclein, the protein known to be the main driver of Parkinson's disease, and mice treated with NLY01. Similar untreated mice that received alpha-synuclein showed marked motor impairment over six months in behavioral tests such as the pole test, which allows researchers to measure motor impairments such as those caused by Parkinson's disease. found that mice treated with NLY01 maintained normal physical function and had no loss of dopaminergic neurons, indicating that the drug protected against the development of Parkinson's disease

transgenic mice alpha-synuclein

mice that have been genetically engineered to naturally produce more human-type alpha-synuclein typically used to model human Parkinson's disease that is prevalent in families

Under normal conditions, these so-called transgenic mice will succumb to the disease in 387 days. However, the Dawson team found that treatment with NLY01 prolonged the life of the 20 mice treated with the drug by more than 120 days.

The Dawson team found that the brains of NLY01-treated mice showed few neurodegenerative signs.

Dawson warns that the investigational drug must still be tested for its safety and efficacy in humans, but based on the safety profile of other similar drugs, it does not foresee any major impediments to its use in the human.

NLY01

Dawson says that he and his team have reason to hope that NLY01 could, in a relatively short period of time, have an impact on the lives of people with Parkinson's disease.

approved by the Food and Drug Administration for the treatment of type 2 diabetes include exenatide, lixisenatide, liraglutide and dulaglutide, each of which can cost around $ 2,000 for a 90-day supplement. there. NLY01 is a long-acting drug with improved brain penetration compared to these approved diabetes medications.

Parkinson's disease is a progressive disorder of the nervous system that affects about 1 million people in the United States, according to the Parkinson Foundation. Early symptoms include tremors, sleep disturbances, constipation, and movement or gait disturbances, which eventually give way to more severe symptoms such as loss of motor skills and dementia

. but cases have been reported in patients as young as 2 years old.

The work was supported by NIH / NINDS NS38377, Maryland Stem Cell Research Foundation, JPB Foundation, National Institute on Aging, American Parkinson Disease Association (APDA)

Seung Pil Yun, et al
Block of conversion of astrocytes A1 by microglia is neuroprotective in models of Parkinson's disease
Nature Medicine (2018)

Image: Simon Beggs, Images of Wellcome