Improvement of Adeno-Associated Virus (AAVs)- and Nano-Particle-Based Technologies by Cell Penetrating Penta-Peptides (CPP5s)

Adeno-Associated Viruses (AAVs) and nanoparticles have been used to deliver DNA or RNA to target cells for gene therapy technologies. These vectors are also useful for DNA- or RNA-based vaccines. Although AAVs and nanoparticles are promising technologies, two major technical problems remain. One problem is that the commonly used AAVs have a low efficiency to penetrate the blood-brain-barrier (BBB) and the blood-retina-barrier (BRB). Consequently, gene delivery to the nervous system has limitations. Another problem is that AAVs induce immune reactions that cause serious side effects. To avoid immune reactions, the AAV dose must be reduced to lower levels that may result in insufficient gene delivery. To overcome these problems, researchers searched for effective peptide sequences by modifying viral capsid proteins. As a result, Cell Penetrating Penta-Peptides (CPP5s) have been shown to be effective in improving the BBB/BRB penetration of AAV and the suppression immune reactions against AAV. CPP5s were originally developed from peptide sequences of Bax (a pro-apoptotic protein) binding domain of Ku70 (a DNA repair protein) and from negative control cell penetrating peptides without Bax-binding activity. This article will discuss the background science of CPP5 and the future direction of the use of CPP5 for AAV- and nanoparticle-mediated gene delivery to the nervous system as well as other organs.