Comparing RNA and protein processing in gene therapy using dual AAV in a mouse model of inherited deafness

The AAV1-intein system rescued the hearing of Otofmice to 35-70 dB, surpassing the efficacy of the AAV1-AK system.

• Pathological mutations in the OTOF gene cause autosomal recessive deafness 9 (DFNB9).
• Different recombination strategies were tested to enhance the effectiveness of OTOF gene therapy.
• The AAV1-AK system improved hearing in Otofmice to 55-70 dB, while the AAV1-intein system achieved 35-70 dB.
• Hearing improvements from the AAV1-intein system lasted up to 12 months post-injection in both newborn and adult mice.
• The AAV1-intein system demonstrated superior efficacy in otoferlin re-expression and restoration of ribbon synapses compared to AAV1-AK.
• These findings suggest that protein recombination may be more effective than nucleic acid recombination for gene therapy in DFNB9.

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