The company revealed that inhibiting an enzyme called stearoyl-CoA desaturase can protect human neurons from alpha-synuclein-derived toxicity and improve their survival.
Based on these promising results, the company plans to initiate the first-in-human clinical trial of its most advanced experimental therapy, YTX-7739, in the fourth quarter of 2019.
The findings were reported in the study, “Inhibiting Stearoyl-CoA Desaturase Ameliorates α-Synuclein Cytotoxicity” published in the journal Cell Reports.
Previous research had found that certain fat molecules, called unsaturated fatty acids, are important mediators of the neurotoxicity caused by the protein alpha-synuclein — a key constituent of Lewy bodies, protein clumps that are a hallmark of Parkinson’s disease.
Importantly, in cell and animal models of the disease, inhibiting the enzyme stearoyl-CoA-desaturase (SCD), key for the production of unsaturated fatty acids (specifically palmitoleic and oleic), could protect against the formation of alpha-synuclein aggregates and its related toxicity.
Using Yumanity’s drug discovery platform, researchers screened for compounds that could protect against alpha-synuclein-induced toxicity. They found a series of small molecules — including YTX-7739 — that was able to rescue yeast cells from the cellular defects and growth impairments caused by alpha-synuclein. YTX-7739 worked by blocking SCD, further supporting the enzyme as a potential therapeutic target for Parkinson’s.
SCD is the first potential target identified by Yumanity’s discovery engine, a group of screening platforms based on yeast and human neurons aimed at finding new and druggable targets for difficult-to-treat, protein misfolding-related neurodegenerative diseases including Parkinson’s, Alzheimer’s and amyotrophic lateral sclerosis (ALS).
The team confirmed its hypothesis in a laboratory model of human neurons derived from pluripotent stem cell (iPCS). iPSCs are derived from either skin or blood cells that have been reprogrammed back into a stem cell-like state, which allows for the development of an unlimited source of any type of human cell needed for therapeutic purposes.
When these model neurons were treated with a commercially available inhibitor of SCD, the neurodegenerative effects of alpha-synuclein were reduced and the cells lived longer. As expected, this protective effect was linked to a decrease in the levels of unsaturated fats inside neurons.
Even though it seems like a promising therapeutic approach to explore, its “precise mechanism of protection is not entirely defined” researchers wrote.
Fatty acids, and oleic acid in specific, are crucial components of cell membranes — both the plasma membrane, which separates the interior of cells from the outside environment, and membranes that enclose crucial structures within the cell.
Based on this knowledge and the study’s results, researchers propose three possible mechanisms for the protective effects of blocking SCD: a toxic increase in fatty acid desaturation is directly reversed by SCD inhibition; reduced fatty acid desaturation (a consequence of blocking SCD) reverses the toxic effects of alpha-synuclein on membrane properties or transport processes within the cell (cellular trafficking); or the reduced fatty acid desaturation enhances a direct toxic interaction of alpha-synuclein with cell membranes.
“The lack of effective new disease-modifying treatments for these disorders stems largely from a scarcity of novel drug targets, and a poor understanding of disease biology,” Ken Rhodes, PhD, chief scientific officer of Yumanity Therapeutics and senior author of the study, said in a press release.
“These new findings are important because they pinpoint a novel mechanism underlying alpha-synuclein toxicity and offer a potential new therapeutic approach to treating Parkinson’s disease through the inhibition of SCD activity,” he said.