# The delivery challenge of adeno-associated virus vector-based gene therapies for neurological diseases

## TL;DR

This paper reviews progress in using AAV viruses to deliver gene therapies to the brain, focusing on overcoming the blood-brain barrier for treating neurological diseases.

## Contribution

The paper provides an updated review of AAV capsid engineering and delivery strategies for CNS gene therapies.

## Key findings

- AAV9 capsids naturally cross the blood-brain barrier and have been used successfully in treating spinal muscular atrophy.
- In vitro models are being developed to predict AAV capsid ability to cross the human blood-brain barrier.
- Strategies to bypass delivery limitations of current AAV vectors are being explored.

## Abstract

There is great anticipation that gene therapies can offer solutions to many neurological diseases. Already, much is known about therapeutic targets and how they would need to be manipulated to mitigate disease. For such gene therapies to move to the clinic, potent CNS delivery vehicles are needed. One line of investigation focuses on adeno-associated viruses (AAV) to address this need. In particular, blood–brain barrier (BBB)-penetrant AAV capsids are of interest due to the relative ease of their intravenous administration. This review will introduce this topic and provide an update on recent developments. First, we describe the physical barriers that must be overcome for AAV-delivered gene therapies to reach target cells in the CNS. We then put a spotlight on the natural AAV9 capsid’s inherent propensity to cross the BBB and key lessons learned from its use for delivering a therapeutic payload for the treatment of spinal muscular atrophy. Next, we summarize methods for engineering recombinant AAV (rAAV) capsids with improved brain penetrance, and present in vitro paradigms for predicting their capacity to cross the human BBB. We also present strategies for side-stepping the delivery limitations of existing rAAV vectors. Finally, we point toward a few notable clinical studies whose outcomes may advance our understanding of what rAAV-delivered gene therapies can offer to people afflicted with CNS disorders.