AAV capsid variants with brain-wide transgene expression and decreased liver targeting after intravenous delivery in mouse and marmoset

The authors developed AAV capsids for robust transgene expression in the brain with decreased liver targeting after non-invasive administration in mice and marmosets, enabling more targeted systemic gene delivery to the brain. Genetic intervention is increasingly being explored as a therapeutic option for debilitating disorders of the central nervous system. The safety and efficacy of gene therapies rely upon expressing a transgene in affected cells while minimizing off-target expression. Here we show organ-specific targeting of adeno-associated virus (AAV) capsids after intravenous delivery, which we achieved by employing a Cre-transgenic-based screening platform and sequential engineering of AAV-PHP.eB between the surface-exposed AA452 and AA460 of VP3. From this selection, we identified capsid variants that were enriched in the brain and targeted away from the liver in C57BL/6J mice. This tropism extends to marmoset (Callithrix jacchus), enabling robust, non-invasive gene delivery to the marmoset brain after intravenous administration. Notably, the capsids identified result in distinct transgene expression profiles within the brain, with one exhibiting high specificity to neurons. The ability to cross the blood-brain barrier with neuronal specificity in rodents and non-human primates enables new avenues for basic research and therapeutic possibilities unattainable with naturally occurring serotypes.

Automated summary

The study developed AAV capsids that achieved robust transgene expression in the brain with decreased liver targeting after non-invasive administration, enabling more targeted systemic gene delivery. This organ-specific targeting extends to marmosets, allowing for non-invasive gene delivery with distinct transgene expression patterns. The ability to cross the blood-brain barrier with neuronal specificity in rodents and non-human primates opens up new avenues for basic research and therapeutic possibilities beyond naturally occurring serotypes.