Study Rationale: A hallmark characteristic of Parkinson’s disease (PD) is the accumulation of alpha-synuclein, a small lipid-binding protein involved in transporting lipids and proteins throughout the cell. This pathology is reduced by inhibition of Stearoyl CoA-Desaturase (SCD), an enzyme involved in lipid metabolism. However, the buildup of alpha-synuclein and the presence of SCD varies among different types of brain cell. These differences suggest that SCD inhibitors may have unique effects on alpha-synuclein pathology or SCD activity in different cellular contexts.
Hypothesis: We hypothesize that distinct brain cell types may respond differently to alpha-synuclein accumulation and to SCD inhibition; these differences could facilitate the discovery of potential new disease targets and clinical biomarkers.
Study Design: We have developed a candidate drug, YTX-7739, that inhibits SCD. In this study, we will test YTX-7739 in multiple preclinical models that differ in how alpha-synuclein is made, including those in which the protein is produced by cells that help neurons function efficiently. In addition to exploring alpha-synuclein itself, we will use single-cell sequencing technologies to characterize the effects of both alpha-synuclein and YTX-7739 on gene expression in diverse brain cell types.
Impact on Diagnosis/Treatment of Parkinson’s disease: These studies will reveal how YTX-7739 affects alpha-synuclein toxicity in multiple brain cell types and how people with PD may best respond to SCD inhibition. Furthermore, these translational studies will provide potential biomarkers that could improve our ability to monitor YTX-7739 activity and disease modification in individuals with PD.
Next Steps for Development: Although YTX-7739 is currently in Phase I/Ib clinical trials, the described studies will directly inform our approach to selecting subjects for future trials, trial design, and biomarker strategy for a Phase II clinical study of diseases caused by synuclein toxicity.