Neonatal AAV gene therapy rescues hearing in a mouse model of SYNE4 deafness.

Summary

A direct genetics-to-therapy test: SYNE4 mutations cause progressive childhood deafness by mislocalizing the nucleus inside hair cells. Delivering a working copy of Syne4 via the AAV9-PHP.B vector to newborn Syne4-knockout mice prevented hair cell degeneration, nearly fully restored auditory brainstem response thresholds, and recovered sound-driven behavior, providing proof of concept that a gene identified through Avraham's genetics work can be corrected with gene therapy before hearing loss sets in.

Key findings

• SYNE4 mutations cause hair cell nucleus mislocalization and progressive hearing loss.
• AAV9-PHP.B-delivered Syne4 gene therapy was injected into the inner ears of newborn Syne4-knockout mice.
• Treated mice showed near-complete recovery of auditory brainstem response thresholds and hair cell survival.
• Sound-evoked behavioral responses were also restored, supporting functional as well as physiological rescue.