Figure 2. Principles of AAV-mediated gene therapy.

Adeno-associated virus (AAV) binds to the host glycosylated cell surface receptor to trigger clathrin-mediated endocytosis internalization. The AAV then moves through the cytosol via the cytoskeletal network. Conformational changes are then triggered by pH changes in the cellular environment, leading to endosomal release. The AAV undergoes transport to the nucleus, releasing its cargo, where it is then transcribed into double-stranded DNA for transcription, or undergoes integration to the host genome (which rarely occurs). Messenger RNA produced from transcription of the cargo leads to its translation to the protein-of-interest outside of the nucleus. Production of this protein-of-interest then enables the cardioprotective effects that are observed in response to AAV-mediated gene therapy.