Project Details
Early Career
Status: Funded - Open
Human neuron models for Mitchell Syndrome therapeutic development
Zita Hubler, MD, PhD
Summary
BACKGROUND: Mitchell Syndrome is a fatal childhood-onset neurodegenerative disorder caused by a gain-of-function in peroxisomal acyl-coenzyme A oxidase 1 (ACOX1) enzyme and characterized by ataxia, hearing loss, and paralysis. Mitchell Syndrome typically results in death within the second decade of life due to a lack of effective therapeutic interventions. GAP: Despite having candidate therapeutics, efforts to treat Mitchell Syndrome are stalled by a lack of human neuron models. HYPOTHESIS: I hypothesize that iPSC-derived Mitchell Syndrome sensory neurons will exhibit phenotypic, transcriptional, and lipid differences, as compared to their CRISPR-corrected controls. Using these differences, I can evaluate the efficacy of the therapeutics we generated. METHODS: I will differentiate our three paired patient-derived iPSC and control lines into sensory neurons. Using immunofluorescence, I will confirm that the cells express sensory neuron-specific proteins and analyze differences in survival. I will evaluate the transcriptional profile between the paired lines. Finally, to evaluate for metabolic differences, I will measure substrates and products of ACOX1 with an established mass-spectrometry assay. I expect Mitchell Syndrome sensory neurons to show impaired survival, differential expression of proteins that regulate ACOX1 activity, and increased abundance of specific ACOX1 lipid products. RESULTS: Pending. IMPACT: This work will advance child health research and clinical practice by enabling the preclinical evaluation of candidate therapeutics for this lethal and tragic disease. For other neurodegenerative diseases, demonstration of therapeutic efficacy in iPSC-based disease-relevant cell models has been sufficient to progress therapeutics toward toxicology studies and clinical trials. Optional/Additional Comments: We want to thank the Mitchell and Friends Foundation for their ongoing advocacy and the participants for their donations.