Many genes mutated in hereditary deafness are expressed in the sensory hair cells of the cochlea, so for gene therapy strategies that might treat these, a viral vector like AAV must efficiently transduce the hair cells. Many different AAV capsids will transduce the inner hair cells of the cochlea in mouse, but most are not efficient for the outer hair cells. Collaborating with Dr. Casey Maguire at Massachusetts General Hospital, we have tested a variety of novel AAV capsids developed by the Maguire laboratory or others.  We found that two, AAV9-PHP.B and AAV-S, transduce both inner and outer hair cells of the cochlea and hair cells of the vestibular system in neonatal mouse. We found they also efficiently transduce hair cells of adult nonhuman primates, suggesting that they may be good vectors for delivery of therapeutic genes to hair cells in humans.

Some common forms of hereditary deafness are caused by genes expressed not in hair cells but in surrounding epithelial cells or fibrocytes. AAV9-PHP.B and AAV-S are also good at delivering genes to these cell types.

AAV structure. A space-filling model of AAV2, constructed by others from X-ray crystal structures of capsid proteins. We found that AAV capsids, especially AAV9-PHP.B and AAV-S, can be good vectors for delivery of therapeutic genes to inner ear hair cells.

PAPERS

György B, Meijer EJ, Ivanchenko MV, Tenneson K, Emond F, Hanlon KS, Indzhykulian AA, Volak A, Karavitaki KD, Tamvakologos PI, Vezina M, Berezovskii VK, Born RT, O'Brien M, Lafond JF, Arsenijevic Y, Kenna MA, Maguire CA, Corey DP. (2018) Gene Transfer with AAV9-PHP.B Rescues Hearing in a Mouse Model of Usher Syndrome 3A and Transduces Hair Cells in a Non-human Primate. Mol Ther Methods Clin Dev. 13:1-13.

Ivanchenko MV, Hanlon KS, Devine MK, Tenneson K, Emond F, Lafond JF, Kenna MA, Corey DP, Maguire CA. (2020) Preclinical testing of AAV9-PHP.B for transgene expression in the non-human primate cochlea. Hear Res. 394:107930.

Ivanchenko MV, Hanlon KS, Hathaway DM, Klein AJ, Peters CW, Li Y, Tamvakologos PI, Nammour J, Maguire CA, Corey DP (2021). AAV-S: A versatile capsid variant for transduction of mouse and primate inner ear. Mol Ther Methods Clin Dev. 21:382-398.