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The overlapping approach was developed recently to expand the adeno‐associated viral (AAV) packaging capacity. In this approach, a gene is split into two partially overlapping fragments and separately packaged into an upstream and a downstream vector, respectively. Transgene expression is achieved in co‐infected cells after homologous recombination. Despite the promising proof‐of‐principle results in the lung, the efficiency has been very disappointing in skeletal muscle. Here we examined two potential rate‐limiting factors including AAV serotype and the transgene sequence.

To study serotype effect, we delivered AAV‐2, ‐5 and ‐6 overlapping vectors (5 × 10⁸ vg particles of the upstream and the downstream vectors, respectively) and 5 × 10⁸ vg particles of the intact gene vector to the tibialis anterior muscles of 7‐week‐old C57Bl/6 mice, respectively. To determine the effect of …