Library-selected AAV variants can effectively translate to non-human primates in the spinal cord and cochlea

AAV peptide display libraries allow for the generation of novel variants capable of high-level transduction. We previously described an AAV peptide display library combined with a sensitive transduction reporter, iTransduce, that enabled the discovery of potent capsids in the mouse brain after only two rounds of selection via intravenous injection. Analogous to drug repurposing, AAV capsids can be used for gene delivery applications other than originally intended. With that in mind, we tested two of the capsids, AAV-F and AAV-S, from our selection in mice to transduce non-human primate (NHP) spinal cord and cochlea, respectively. We found that intrathecally injected AAV-F mediated higher expression in motor neurons and interneurons compared to AAV9 in the thoracic and lumbar regions, despite lower numbers of genomes per cell in AAV-F-treated animals. AAV-S was tested in the inner ears of mice and cynomolgus macaques, and in both cases drove robust, high-level transduction throughout the cochlea. Further, AAV-S was able to rescue the deafness phenotype of a mouse model of Clarin-1 related Usher Syndrome. Overall, this work serves to highlight that AAV variants selected from our library system can translate effectively to clinically relevant large animals, and provides further evidence for the benefits of capsid repurposing.

Learning Objectives:

1. Recall that AAV libraries allow for the selection of potent new variants; however, most of these are only extensively tested in mouse

2. Recognize the testing of two previously selected variants, AAV-F and AAV-S, in cynomolgus macaques

3. Restate how AAV-F expressed well in the spinal cord even at low doses, with slightly higher levels of expression compared to AAV9 despite lower per-cell genome numbers.

4. Indicate that AAV-S drove high level expression in the inner ears of mice and macaques, and was able to robustly rescue deafness in a mouse model of Clarin-1 Usher syndrome