UC San Diego

Parkinson’s Disease (PD) is an age-related neurodegenerative disease characterized by tremors, bradykinesia, and rigidity. While several pharmaceutical therapies have been developed to address PD symptoms, there are no preventative treatment or therapies available. To address this gap, Kainos Medicine, Inc. developed KM-819, a FAF-1 inhibitor currently in phase 2 clinical trial1,2. In order to understand the mechanistic effects of this drug in humans early in the disease course, this research utilizes an iPSC model derived from Gaucher Disease (GD) patients – a population shown to acquire PD at significantly higher rates than the general population3. Specifically, live-cell imaging techniques are used to explore the quantity and morphology of lysosomes and mitochondria in GD and healthy control (HC) cell lines, with and without KM-819 treatment. This model system has been explored previously; 24h treatment with 1-20µM KM-819 was found to increase lysosome size and motility, with the most significant improvement consistently occurring around 1µM4. In order to explore the efficacy of KM-819 at low dosages, cells were treated for 24h with 0.1 µM KM-819 and imaged using LysoTracker. Consistent with previous findings, lysosome size and quantity both increased, even at low dosage. Next, the mitochondrial system was explored as it is frequently implicated in PD. Initial experiments focused on establishing baseline measurements for untreated cells; morphological analysis indicated that GD mitochondria present with increased fragmentation and reduced network complexity compared to HC cells. Treating GD cells with 0.1µM of KM-819 for 24h showed significant reductions in mitochondria fragmentation and increased network complexity.