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Precise gene editing as a therapeutic approach in cardiac disease

Subject Area Cardiology, Angiology
Term from 2021 to 2023
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 497272873
 
Final Report Year 2024

Final Report Abstract

Cardiovascular diseases are the most common cause of death in our society, which highlights the need for new therapies. Increased and sustained CaMKIIδ overactivation has been shown to be a main indicator and inducer of various cardiac diseases, thereby offering a promising therapeutic target. However, conventional compound-based strategies often face significant limitations (poor isoform- and organ-specificity, poor bioavailability, etc.) that preclude clinical translation, which is also the case for current CaMKIIδ inhibitors. To overcome these challenges, we conceived the idea of using CRISPR-Cas9 gene editing to modulate the CaMKIIδ signalling pathway. First, we edited the CaMKIIδ autophosphorylation site in the mouse germline, which protected mice from heart failure-related mortality and deterioration of cardiac function. With respect to potential clinical translation, we then generated a humanized CaMKIIδ knockin mouse model to deploy the editing strategies optimized for the human genome in vivo in mice. We hypothesized that CaMKIIδ editing could also be beneficial postnatally and in other cardiovascular disease entities. Therefore, we developed a strategy to ablate the oxidative activation sites of CaMKIIδ to confer cardioprotection against high oxidative stress as it occurs during a heart attack. Indeed, editing CaMKIIδ after a heart attack enabled adult mice to recover cardiac function, improved exercise capacity, and protected from myocardial fibrosis. Use of a heart-specific troponin T promoter restricted the editing exclusively to cardiomyocytes, thereby reducing the risk of potential side effects. Previous gene editing approaches aimed to correct single pathogenic mutations that are typically very rare and may affect only a few families, which precludes broad application. In our work, we describe a new concept in which CRISPR-Cas9 gene editing is deployed to disrupt a common pathological signalling pathway during adulthood that could be applied to a wide range of patients with heart disease. We believe that this concept can also be extended to other diseases above and beyond the heart. CaMKIIδ gene editing may thus represent an advanced strategy for heart disease therapy.

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