The ongoing evolution and translational potential of novel AAV vectors for human gene therapy

Recombinant adeno-associated viral (AAV) vectors have irrefutably taken the lead in gene therapy clinical trials, gaining overwhelming popularity in the past decade as a result of their ability to safely mediate long-term expression and efficacy. While the FDA’s approval of Luxturna last year and the wave of Phase 1/2 studies coming down the clinical pipeline are strong testaments to the therapeutic promise of AAV-based gene therapy, improvements in delivery efficiency, target specificity and resistance to neutralizing antibodies of AAV vectors in humans are crucial for expanding patient eligibility and adapting the technology to a broad range of diseases. AAV’s minimalistic genome, in which all capsid proteins are encoded by a single gene, has enabled accelerated development of capsid design and evolution strategies, culminating in recent FDA clearance of several novel AAV variants for use in clinical studies. This review describes the latest trends in AAV vector engineering that harness cell-type-specific selection schemes and our rapidly accumulating knowledge of AAV capsid structure and function to overcome longstanding obstacles in the gene therapy field. Next-generation sequencing platforms that have powered unprecedented, high-throughput phenotypic profiling of AAV vectors are also discussed. As these innovations fuel the remarkable momentum in the field, outstanding challenges in scalable manufacturing, immune evasion, and translation of transduction potency across species will shape the ongoing evolution of novel AAV vectors.

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