Development of Gene Therapy Vectors: Remaining Challenges

Abstract Almost 20 years after the tragic death of a young patient due to an experimental gene therapy trial to treat Ornithine Transcarboxylase deficiency, the FDA approved its first landmark gene therapy drug i.e. Luxturna® to treat inherited blindness, and dozens of gene therapy studies are underway. Whether it is replacing the mutant copies of the gene with the wild type one or editing the mutant one in or ex-vivo to elicit the production of functional proteins, numerous viral and non-viral vectors for delivering the gene payload are being evaluated. While, non-viral vectors avoid or mitigate limiting factors such as immunogenicity and the presence of neutralizing antibodies (NAbs), viral vectors such as recombinant adeno-associated viruses (AAVs) have shown early success as a delivery vehicle, because of the overall safety, target specificity, and long-term stability profile. Nonetheless, multiple challenges during the AAV product development and approval process are still looming. AAV serotypes are continuously being engineered which requires multiple cell-based assays to not only assess the neutralizing antibodies (NAb) seroprevalence but also to develop the in-vitro bio potency assays. Hence, we focus on some critical aspects of the AAVs that determine the path forward for pre-clinical and clinical product development.