Evaluating iPSC-Derived Models to Study and Treat Mitchell Syndrome

Mitchell Syndrome is a progressive childhood-onset neurodegenerative disorder characterized by sensory ataxia, hearing loss, skin changes, and eventual paralysis and encephalopathy, typically leading to death within the second decade of life. The first patient with Mitchell Syndrome was treated at Washington University in St. Louis (WashU), which makes WashU uniquely situated for researching this rare disease. WashU sees around 30% of known patients, has characterized the disease's natural history, and has extensive resources such as post-mortem tissues and a biofluid biobank. Our long-term goal is to develop effective treatments for Mitchell Syndrome. The disease is caused by an autosomal dominant variant in ACOX1, leading to a gain-of-function in the acyl-CoA oxidase 1 (ACOX1) protein. Our preliminary studies indicate that the variant impacts both sensory neurons and oligodendrocytes. Patient-derived induced pluripotent stem cells (iPSCs) offer a scalable, homogeneous platform for modeling rare diseases and evaluating precision-medicine therapeutics. We aim to develop iPSC-derived models of oligodendrocytes and sensory neurons to recapitulate Mitchell Syndrome as a tool to evaluate potential treatments. Preliminary data from patient-derived iPSC lines show transcriptional and metabolic abnormalities linked to the disease variant. We propose two specific aims: Aim 1: Evaluate ACOX1 gain-of-function in iPSC-derived oligodendrocytes. Aim 2: Investigate ACOX1 gain-of-function in iPSC-derived sensory neurons. Mitchell Syndrome intertwines lipid metabolism, oxidative stress, and neuronal/glial degeneration. This project aims to provide essential models for therapeutic evaluation, leveraging WashU's unique expertise and resources. At the culmination of this project we will have two scalable, disease-relevant, human models of Mitchell Syndrome that can be used for mechanistic studies, therapeutic development, and biomarker exploration – critical steps on the way to treat this lethal and tragic disease. Project Number: 1R21NS148869-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: TIMOTHY MILLER | Institution: WASHINGTON UNIVERSITY, SAINT LOUIS, MO | Award Amount: $427,625 | Activity Code: R21 | Study Section: Therapeutic Approaches to Genetic Diseases Study Section[TAG] View on NIH RePORTER: https://reporter.nih.gov/project-details/11355120