Alex Li

Program: Molecular Genetics and Genomics

Current advisor: Fumihiko Urano, MD, PhD

Undergraduate university: Washington University, 2021

Enrollment year: 2023

Research summary
Leveraging base editing to treat Wolfram sryndrome

My research centers on understanding how mutations in the Wolfram syndrome 1 (WFS1) gene contribute to β-cell dysfunction and the development of monogenic diabetes. WFS1 encodes an endoplasmic reticulum (ER)-resident protein involved in maintaining ER homeostasis, and its dysfunction has been implicated in ER stress, impaired insulin secretion, and eventual β-cell failure. Despite this, the precise molecular mechanisms linking WFS1 mutations to disease pathogenesis remain incompletely understood.

To address this, I use CRISPR-based genome editing to engineer human stem cell-derived β-cell models that carry clinically relevant WFS1 mutations. I then apply a combination of proteomic profiling, transcriptomic analysis, and functional assays (e.g., glucose-stimulated insulin secretion, ER stress response assays) to examine how these mutations alter cellular pathways. My goal is to identify how specific WFS1 variants impact β-cell identity, resilience to stress, and secretory function. And to also deivse a in-vitro as well as in-vivo plateform for applying Base editing techonology into treating and curing pathogenic missense mutation in wolfram syndrome.

Through this work, I aim to define the molecular underpinnings of WFS1-related β-cell dysfunction and to identify potential targets for therapeutic intervention. More broadly, this research contributes to our understanding of ER stress-related mechanisms in diabetes and supports the development of personalized approaches to treating monogenic forms of the disease.

Graduate publications
Li Z, Gallardo-Pinera J, Lu C, Mukherjee N, Ouyang W, Millman JR, Banksota S, Remedi MS, Urano F. 2026 Leveraging Base-editing to Treat Wolfram Syndrome: A Monogenic Model of Diabetes, Neurodegeneration, and Optic Atrophy.. , ():

Li Z, Gallardo-Pinera J, Lu C, Mukherjee N, Ouyang W, Millman JR, Banskota S, Remedi MS, Urano F. 2026 Leveraging Base-editing to Treat Wolfram Syndrome: A Monogenic Model of Diabetes, Neurodegeneration, and Optic Atrophy. , ():

Li Z, Gallardo-Pinera J, Lu C, Banskota S, Remedi MS, Urano F. 2025 Leveraging Gene Therapy as a Potential Cure for Wolfram Syndrome – a Monogenic Model for T2DM, Neurodegeneration, and Retinal Atrophy. , ():

Li Z, Gallardo-Pinera J, Lu C, Mukherjee N, Ouyang W, Liimatta E, Millman JR, Banskota S, Remedi MS, Urano F. 2025 Leveraging Gene-editing Therapy for Ashkenazi Jewish Subtype of Wolfram Syndrome. , ():

Yen A, Sarafinovska S, Chen X, Skinner DD, Leti F, Crosby M, Hoisington-Lopez J, Wu Y, Chen J, Li ZA, Noguchi KK, Mitra RD, Dougherty JD. 2024 MYT1L deficiency impairs excitatory neuron trajectory during cortical development. Nat Commun, 15(1):10308. PMCID: PMC11603064

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