Abstract: Hybrid adeno-associated virus (AAV) vector systems able to efficiently express therapeutic target genes larger than may be carried in a single AAV vector are provided, wherein a highly recombinogenic foreign DNA sequence is incorporated into two or more ITR-mediated AAV vectors. In one aspect of one embodiment, the novel hybrid AAV vector system is a hybrid dual AAV (hdAAV) vector system. In another aspect of one embodiment, the novel hybrid AAV vector system is a hybrid tri AAV (htAAV) vector system. A method of treating a clinical disease caused at least in part by a defective gene is provided, and comprises (1) providing a hybrid AAV vector system capable of expressing a therapeutic target gene, wherein the therapeutic target gene is capable of replacing, restoring or counteracting the effects of the defective gene; and (2) administering a therapeutic amount of said vector system to a subject wherein said therapeutic target gene is expressed at levels having a therapeutic effect.