In Vivo, Non-Viral Base Editing To Correct AT Variants In Brain, Blood, Lung, and Liver

Awardee: Xizhen Lian

Institution: Johns Hopkins University

Grant Amount: $41,740

Funding Period: February 1, 2025 - January 31, 2026


Summary:

Ataxia telangiectasia (A-T) is a multi-organ disorder caused by recessive mutations in the ATM gene, which encodes a master regulator of the DNA damage response and impacts redox balance, angiogenesis, and glucose metabolism. In this project we will explore a base editing strategy to correct a pathogenic ATM mutation to initiate the PIs' efforts towards precision gene therapy for treating A-T. Specifically, the PIs have access to ATM patient cells harboring the R2598X mutation, and this variant is amenable to base correction. Employing lipid nanoparticles, the most clinically advanced nonviral gene delivery technology, the PIs will demonstrate in vivo base editor delivery into hematopoietic stem cells, lung and liver to potentially alleviate A-T-related morbidity and mortality. Overall, results obtained with the support of this project will set the stage for future A-T gene therapy studies including the optimization of prime editing strategies to correct ATM and expanding delivery to the central nervous system.

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Deciphering perturbations of primary cilia in Okur-Chung neurodevelopmental disorder

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Investigating Excitation/Inhibition Balance in Cortical-Thalamic Circuitry in CDKL5 Deficiency Disorder Using Human-Derived Assembloids