Onasemnogene abeparvovec administered as a single intravenous dose of 6.7e13 viral genomes/kg resulted in all treated SMA patients achieving superior motor milestones compared to historical controls and sustained survival benefit.
This review highlights the critical challenge of delivering AAV-based gene therapies across the blood-brain barrier for neurological diseases and outlines current capsid engineering strategies to overcome these barriers.
Effect estimate: Superior motor milestones achieved compared to historical cohorts
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.
Pak et al. (Thu,) conducted a review in Pediatric patients with spinal muscular atrophy treated with onasemnogene abeparvovec gene therapy (n=3,000). Onasemnogene abeparvovec (OA, Zolgensma) vs. Historical cohorts was evaluated on Achievement of motor milestones and survival without permanent ventilation (Superior motor milestones achieved compared to historical cohorts). Onasemnogene abeparvovec administered as a single intravenous dose of 6.7e13 viral genomes/kg resulted in all treated SMA patients achieving superior motor milestones compared to historical controls and sustained survival benefit.