THE JEREMIAH METZGER LECTURE: TURNING GENES INTO MEDICINES: HIGHLIGHTS AND HURDLES IN THE DEVELOPMENT OF GENE THERAPY FOR GENETIC DISEASE.

The journey from in vitro transfer of genes into mammalian cells to approved gene therapy products has spanned decades. This manuscript summarizes hurdles encountered and obstacles overcome in the development of successful adeno-associated viral (AAV) vectors for hemophilia B and for an inherited retinal dystrophy caused by mutations in the RPE65 gene. In the case of hemophilia B, careful analysis of the first unsuccessful attempts led to the realization that the human immune response to AAV vectors was preventing durable expression; elucidation of the response to the recombinant virion led to strategies that enabled successful long-lasting gene transfer. For RPE65 deficiency, a key to success was development and validation of a novel clinical endpoint for a disease that previously lacked a pharmacologic treatment.