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Potential Parkinson’s Disease Treatment, YTX-7739 Helps Motor Skills in Mice

A experimental disease-modifying treatment by Yumanity Therapeutics, called YTX-7739, was found to improve motor skills and reduce clumping of toxic proteins in a mouse model of Parkinson’s disease (PD), the company reported in a press release.

Data from this preclinical proof-of-concept study, titled “YTX-7739, a clinical-stage stearoyl-CoA desaturase inhibitor for Parkinson’s disease improves behavioral and pathological features in an a-synuclein mouse model,is being presented this week at the virtual 5th Annual International Conference on Alzheimer’s and Parkinson’s Diseases (AD/PD 2021).

YTX-7739 is a small molecule designed to inhibit the activity of stearoyl-CoA desaturase (SCD), an enzyme involved in lipid metabolism and playing a role in the toxic accumulation of the protein alpha-synuclein, characteristic of Parkinson’s disease and other neurodegenerative diseases.

As a small molecule, YTX-7739 can cross the blood-brain barrier, a selective semi-permeable membrane that protects the brain from viruses and other attacks that can be transmitted by circulating blood.

The treatment has been shown to be safe and well tolerated in a Phase 1 clinical trial in healthy adults. A phase 1b trial, also underway in the Netherlands, is currently evaluating the safety and efficacy of YTX-7739 in people with Parkinson’s disease, Yumanity reported. The first data should be published by the middle of the year.

“SCD inhibition…has been shown to prevent [alpha]-synuclein pathology in multiple models, including patient-derived neurons,” said Dan Tardiff, PhD, acting director of research and scientific co-founder of Yumanity.

“The results of the current study demonstrate that YTX-7739 has a similar effect in a mouse model of Parkinson’s disease pathology,” added Tardiff, who is presenting the data at AD/PD 2021.

The mouse study, conducted in collaboration with researchers at Brigham & Women’s Hospital, evaluated the effectiveness of oral YTX-7739 in reducing motor defects, improving neuron survival and attenuating other characteristics of disease in a mouse model of Parkinson’s disease.

YTX-7739 was administered to Parkinson’s model mice and healthy mice, serving as a control group, from 2 months of age to 6 months of age.

Control mice and Parkinsonian mice showed an 80% decrease in the fatty acid desaturation index in the brain, which measures SCD activity. This decrease in SCD activity was associated with better motor function after four months of YTX-7739 treatment, as shown by the mice’s performance in the climbing and rotarod tests.

Brain levels of YTX-7739 were high enough to block SCD activity, leading to lower levels of potentially disease-related monounsaturated fatty acids in the blood and brain.

Alpha-synuclein levels were significantly reduced in mice treated with YTX-7739 compared to untreated animals. YTX-7739 treatment also improved the survival of dopaminergic neurons that are selectively lost in patients with Parkinson’s disease.

The benefits of The YTX-7739 treatment observed in this mouse model was also observed in patient-derived neurons.

“These data highlight the critical role of lipid biology, particularly saturated fatty acids, in mediating alpha-synuclein pathobiology and support the ongoing clinical evaluation YTX-7739 as a disease-modifying drug for synucleinopathies,” the researchers wrote.

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