Split-AAV gene therapy restores hearing in deaf mice

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Researchers demonstrate the potential of using dual-AAV vectors to deliver large transgenes to mouse inner ear. Through this approach, auditory function of a genetically deaf mice was partially restored.

OTOF gene mutation results in hereditary non‐syndromic hearing loss. OTOF gene encodes Otoferlin, a 6kb-long protein predominantly expressed in the inner hair cells (IHCs). Otof knockout mice were shown to be deaf; otoferlin’s role in IHC exocytosis and vesicle formation is thought to be the mechanism behind it.

Recombinant adeno‐associated viruses (AAVs) provide a safe and promising gene therapy tool to treat deafness. However, AAV vectors are incapable of delivering large transgenes like otoferlin. Although dual- and triple AAV vectors have shown efficacy in photoreceptors and muscle cells, these approaches have not been tested in ear cells.

In the present study published in EMBO Molecular Medicine, Dr Ellen Reisinger and team at the University of Gottingen investigated whether delivery of otoferlin cDNA through dual-AAV vectors can restore defective IHC and auditory function in Otof−/− mice. To achieve this, otoferlin coding sequence was split into two and were packaged into two separate AAV vectors, each containing half of the otoferlin cDNA. These were then co-injected into the cochlea of 6-7 days old otoferlin knockout mice and it resulted in the expression of full-length otoferlin in up to 50% of IHCs. Fast exocytosis was fully rescued, leading to restoration of synaptic and auditory function.

The study provides proof of concept that dual‐AAV vectors are suitable for the delivery of large transgenes such as otoferlin into mammalian IHCs and can at least partially restore auditory function.

Further studies to determine the best AAV vectors for the split approach and optimization of the injection procedure are required to advance this to future gene replacement therapies of recessively inherited deafness.

Source: A dual-AAV approach restores fast exocytosis and partially rescues auditory function in deaf otoferlin knock-out mice. Al-Moyed H et al.,EMBO Molecular Medicine, December 2018. DOI