Previous research in mice has demonstrated that specific modifications of the outer surface of the AAV capsid greatly increase the ability of AAV to cross the blood-brain barrier and deliver the desired gene therapy to the brain. These capsid modifications are performed by editing the genes which encode the viral capsid proteins. The drawback is that the specific AAV capsid modifications from previous research only work in mice, but do not work when tested in non-human primates. In the context of the lock and key analogy, the mouse and human blood-brain barriers are differing locks which consequently require different keys for entry.

​Research by STEM Biomedical colleagues Alexander Ille, Raoul Bodea, Anetta Ille, and collaborating peers aims to extend the ability of engineered AAVs to cross the blood-brain barrier beyond only working in mice. This research was recently published in the Journal of NeuroVirology, part of Springer Nature (Ille et al., 2020). The goal of this research is to advance efforts for engineering an AAV capable of efficiently crossing the blood-brain barrier for safe and effective gene therapy applications in humans. Although the research is still in an exploratory stage, progress is being made.

Through the use of various bioinformatic tools, the researchers identified a receptor in the human blood brain barrier which appears to be similar to the receptor responsible for the improved transport of AAV across the mouse blood-brain barrier. This data was used to computationally engineer AAV for crossing the human blood-brain barrier by a similar receptor mechanism as in mice. Simulations of binding between this engineered AAV and the desired human receptor appear promising, yet further research is needed. Despite the preliminary nature of the study, the researchers hope their work will help accelerate the development of successful therapeutic strategies for combating disorders of the brain.