Advancing CRISPR gene therapy for Noonan syndrome: Targeting recurrent LZTR1 variants with all-in-one Cas9 and base editors in patient-derived iPSC-cardiomyocytes

by Carolin Knauer
Cumulative thesis
Date of Examination:2025-05-20
Date of issue:2025-05-28
Advisor:Dr. Lukas Cyganek
Referee:Dr. Lukas Cyganek
Referee:Prof. Dr. Wolfram-Hubertus Zimmermann
Persistent Address: http://dx.doi.org/10.53846/goediss-11297

 

 

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Abstract

English

Pathogenic variants in LZTR1 are causative for Noonan syndrome with early onset of a severe hypertrophic cardiomyopathy. Despite high clinical relevance, therapeutic options are highly limited, and no curative treatment exists. In this thesis, different CRISPR-based gene editing approaches were evaluated in a preclinical model of Noonan syndrome-associated hypertrophic cardiomyopathy based on patient-derived induced pluripotent stem cells differentiated into ventricular cardiomyocytes. The findings revealed that classical CRISPR-Cas9 gene editing was not able to rescue the disease pathology in vitro. In contrast, base editing efficiently corrected the pathogenic variant and rescued LZTR1 function in patient-specific cardiomyocytes, demonstrating a suitable strategy for a curative therapy for Noonan syndrome caused by recessive LZTR1 variants.
Keywords: Noonan syndrome; hypertrophic cardiomyopathy; gene editing; gene therapy; CRISPR-Cas9; Base editing; iPSC-cardiomyocytes