Precision Gene Editing for Muscle Diseases

Muscle, comprising both skeletal muscle and cardiac muscle, is integral to the human experience, allowing us to do the many incredible things. Consequently, genetic mutations that cause muscle disease can have a profound effect on the afflicted individual. Gene editing tools like base editors and prime editors enable us to target and correct the underlying genetic causes of these diseases. Base editors enable precise base pair transition edits, while prime editors offer even more versatility, allowing for base pair transition and transversion edits, as well as short insertions and deletions. Duchenne muscular dystrophy (DMD), a fatal neuromuscular disease of progressive muscle weakness and wasting, is caused by mutations in the DMD gene on the X chromosome, resulting in a lack of dystrophin protein. Affected individuals typically do not survive beyond their thirties. Hypertrophic cardiomyopathy (HCM), on the other hand, is a disease characterized by abnormal thickening of the heart muscle that can progress to heart failure and sudden cardiac death. It is often caused by a dominant-negative mutation in a sarcomere protein, which leads to pathological augmentation of sarcomere contraction. In this dissertation work, I demonstrate the efficacy of base editing and prime editing approaches in targeting a few DNA mutations associated with DMD and HCM. For DMD, I employ exon skipping, a technique that modifies the processing of mature mRNA to produce an internally truncated but functional dystrophin protein. This proof-of-concept approach holds great promise for the treatment of this X-linked recessive disease. For HCM, base editing allows us to correct the DNA point mutation responsible for the disease, converting the pathogenic peptide back to its healthy form. Through in vitro and in vivo studies using models of DMD and HCM, I demonstrate highly efficient correction and rescue of the pathological features associated with these diseases. These findings highlight the potential of gene editing as a targeted and precise therapeutic approach for muscle diseases, and this work represents a significant step forward in developing potential cures for these debilitating muscle diseases.

Author dc:creator

• Chai, Andreas Chenzhang

Contributors dc:contributor

• Chen, Elizabeth
• Olson, Eric N.
• Mendell, Joshua T.
• Chen, Zhijian J.

• Gene Editing
• Genetic Therapy
• Muscular Dystrophy, Duchenne
• Cardiomyopathy, Hypertrophic

Language dc:language

en

Identifier

1535537208

OAI identifier oai:identifier

oai:utswmed-ir.tdl.org:2152.5/10698