Potential Oral Treatment, YTX-7739, Aids Motor Skills in Mouse Model

An investigative disease-modifying treatment by Yumanity Therapeutics, called YTX-7739, was found to improve motor skills and lessen toxic protein clumping 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 that is involved in lipid metabolism and plays a role in the toxic accumulation of alpha-synuclein protein, a hallmark of Parkinson’s 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 insults that might be carried on circulating blood.

The therapy was reported to be safe and well-tolerated in a Phase 1 clinical trial in healthy adults.  A Phase 1b trial, also taking place in the Netherlands, is now evaluating the safety and efficacy of YTX-7739 in people with Parkinson’s, Yumanity reported. Early data are expected to be released by midyear.

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

“The results from the current study demonstrate that YTX-7739 has a similar effect in a mouse model of Parkinson’s disease-related 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, assessed the efficacy of oral YTX-7739 in reducing motor defects, improving neuron survival, and easing other disease features in a mouse model of Parkinson’s.

YTX-7739 was fed to mice in the Parkinson’s model and to healthy mice, serving as a control group, from age 2 months until they were 6 months old.

Both control and Parkinson’s mice showed a decrease of 80% in the brain of fatty acid desaturation index, which measures the activity of SCD. This drop in SCD activity was associated with better motor function after four months of YTX-7739 treatment, as seen in the mice’s performance on pole climbing and rotarod tests.

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

Levels of alpha-synuclein 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 Parkinson’s patients. 

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

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