X35 - Implementing Base Editing to Correct a Pathogenic Variant of Wolfram Syndrome for Preventing Neurodegeneration

Introduction: : Wolfram syndrome (WS) is a rare autosomal-recessive genetic disorder characterized by diabetes mellitus, optic atrophy, hearing loss, and neurodegeneration, primarily caused by pathogenic variants in the WFS1 gene. Current treatment modalities only address symptoms and fail to correct the underlying genetic defect, underscoring the need for innovative therapeutic approaches. This study evaluates the efficacy of base editing, a precise gene-editing technology, in correcting a pathogenic variant the p.W540* variant, that leads to neurodegeneration and other severe symptoms in WS.

Materials and

Methods: : We first examined the in vitro correction of the variant in patient-derived induced pluripotent stem cells (iPSCs) differentiated into neural progenitor cells (NPCs) and cortical neurons with engineered virus-like particles. We then assessed gene editing efficiency and the rescue of cellular dysfunctions associated with loss of function of WFS1, such as endoplasmic reticulum (ER) stress, mitochondrial dysfunction, and apoptosis markers. Finally, we assessed the therapeutic potential of base editing in vivo using a mouse model of WS treated with dual adeno-associated virus (AAV) vectors via intracerebroventricular and subretinal delivery. Behavioral assays were used to assess cognitive and motor functions, while brain tissue analyses focused on markers of neuronal cell death.

Results, Conclusions, and Discussions:: The successful correction of the p.W540* variant in the WFS1 gene is anticipated to mitigate neurodegeneration, attenuate optic atrophy, enhance cell viability, and improve cognitive function, offering a promising one-time therapeutic strategy for WS. This study has the potential to lay the groundwork for developing similar therapies for neurodegenerative and monogenic disorders, advancing the field of precision medicine and gene editing.

Acknowledgements and/or References (Optional)::