Next-generation strategies to improve safety and efficacy of adeno-associated virus-based gene therapy for hemophilia: lessons from clinical trials in other gene therapies

Three major directions for the global progress of adeno-associated virus (AAV) vectors for gene therapies (GT) are analyzed: 1) engineering vectors to increase transgene expression; 2) aligning interests of the health system with costs and challenges for the pharmaceutical industry; and 3) refining patient eligibility criteria and endpoint definition. Currently employed AAV vectors may cause toxicity and adverse events. Furthermore, studies in animals do not fully predict risks and clinical benefits of AAV-based GT, and animal models reflecting the heterogeneity of certain clinical settings (e.g., congestive heart failure) are not widely available for improving AAV-based GT. Finally, antisense and gene editing approaches will soon complement gene augmentation strategies for the stable solution of unsolved issues of AAV-based GT. While minimizing toxicity, next-generation AAV vectors should decrease the viral load needed to achieve therapeutic efficacy, be functional in a restricted cellular subset, avoid transgene expression in unwanted cells (e.g., hepatocytes), and escape immune oversight in AAV-based GT. The role of stress-induced apoptosis in the loss of transgene expression in GT should also be explored. Aligning the interests and obligations of the pharmaceutical industry with those of the health system is critical for the success of AAV-based GT. Costs and challenges for the pharmaceutical industry include: a) removing impurities from AAV; b) validating tests to measure treatment efficacy; c) promoting training programs to standardize vector genome delivery; d) collecting long-term follow-up data; and e) maintaining sustainability and cost-effectiveness of AAV-based GT. In rare disorders with small patient numbers (e.g., hemophilia), clear-cut outcomes are mandatory as endpoints of unequivocal efficacy data.