The DNA packaging capacity of the Adeno-Associated Vectors (AAV) is relatively small, currently rendering it deficient for the treatment of diseases requiring large gene transfer (>4.7kb). To overcome this size limitation, we have developed a novel technique (OAGR) and characterized existing approaches that exploit host DNA repair pathways for intracellular large transgene reconstruction. During this work we have identified host DNA repair proteins and pathways necessary for episomal genetic engineering with the understanding that enhancements at the basic science level will aid in the generation of a safer and more efficient clinical reagent. Towards disease therapy, we have evaluated different AAV large gene delivery contexts in disease models of dysferlinopathy and hemophilia A.