Work

Non-cell-autonomous manner of AAV administration to attenuate cardiomyocyte hypertrophy by targeting paracrine signaling on ECM to reduce viral dosage

Year: 2022

Type: article

Abstract: Adeno-associated virus (AAV) is one of the most powerful vectors for exogenous gene delivery. 1 However, the risks associated with the high dosages of AAV administration that are required to achieve meaningful effects limit the applicability of this method. Generally, AAV only presents cell autonomous manner in infected cells. Besides, mosaic genetic editing or gene therapy would trigger global biological function restore by above 30–40% infective ratio in heart diseases. 2 However, if non-cell-autonomous effect could be achieved for AAV gene therapy, the viral dosage for AAV administration would reduced significantly, avoiding high dosage risks. Extracellular matrix (ECM) remodeling is a response to maladaptive stimuli, especially for exceeding mechanical stress. 3 Increased stiffness of myocardial tissue ECM is associated with enhanced mechanotransduction and activation of integrin/Hippo/Yap signaling. 4 Several cytokines and molecules are involved in ECM remodeling by paracrine manner, including CTGF. Accordingly, we speculated it might be potentially a non-cell-autonomous target to attenuate cardiac hypertrophy by inhibiting Ctgf based on its paracrine character to reduce the dosage of AAV. Besides, micro (mi)RNAs regulate many biological processes and Ctgf transcription, 3 , 5 which is also a perfect nucleotide sequence for AAV delivery. To test this hypothesis, we developed a strategy for AAV-mediated delivery of miRNA targeting Ctgf to reverse the ECM remodeling to attenuate CM hypertrophy and attempt to calculate the minimum dosage of AAV required to achieve a biological therapeutic effect.

Source: Signal Transduction and Targeted Therapy

DOI: 10.1038/s41392-021-00715-z