BME PhD Prospectus Presentation: Christopher Lu

Title: "Implementing Base Editing to Correct Pathogenic Variants of Wolfram Syndrome for Preventing Neurodegeneration & Vision Loss"

Advisory Committee: Samagya Banskota, Ph.D. (BME; MCBB) – Research Advisor Wilson Wong, Ph.D. (BME; MCBB) – Chair Liangliang Hao, Ph.D. (BME; MCBB) Fumihiko Urano, M.D., Ph.D. (Medicine and Pathology & Immunology)

Abstract: Wolfram syndrome (WS) is a rare, life-threatening autosomal-recessive genetic disorder characterized by diabetes mellitus, optic nerve atrophy, hearing loss, and neurodegeneration, primarily caused by pathogenic variants in the Wolfram syndrome 1 (WFS1) gene. Most WS patients have biallelic recessive pathogenic variants in the WFS1 gene; the disease progression manifests with the clinical onset of diabetes mellitus and optic nerve atrophy during early adolescence followed by progressive hearing loss and neurodegeneration resulting in a median age at death of approximately 30 years. Current treatment modalities for rare diseases including WS have largely followed two paths: small molecules that focus primarily on symptom management and require lifelong and costly administration or gene replacement therapy which can lead to subtherapeutic or overexpression leading to neuronal and hepatic toxicity. Herein, we developed a transformative therapeutic strategy for WS by applying base editing, a precise gene-editing technology, to correct the severe WFS1 c.1620C>T (p.W540*) pathogenic variant that leads to diabetes, vision loss, and neurodegeneration among other severe symptoms in WS. Using the knowledge gained we hope to also develop a therapeutic approach to multiplex screening of all WFS1 pathogenic variants that can be resolved by base editing. In Aim 1, we will optimize and develop an adenine base editor (ABE) platform to correct the WFS1 p.W540* pathogenic variant in primary cell models (neuroprogenitor cells, forebrain neurons, and pancreatic β-cell). In Aim 2, we will determine the therapeutic efficacy of in vivo ABE for diabetic, visual, and neurological phenotypes using both viral and non-viral delivery platforms. In Aim 3, we will design a WFS1 pathogenic variant senor library screening approach to multiplex base editor platform discovery to address all the transition point mutations in patients with WS directly supporting therapeutic development for 62.6% of patients in the WS International Registry. Our findings have the potential to lay the groundwork for developing similar therapies for life-threatening, neurodegenerative, monogenic disorders, advancing the field of precision medicine and gene editing.