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The fact that four of the five cell and gene therapy (CGT) drugs approved by the FDA in 2022 utilize adeno-associated virus (AAV) vectors highlights the enormous potential of AAV-based gene therapy for clinical application. The latest additions to the CGT family are Adstiladrin and Hemgenix, which were approved by the FDA in November and December of 2022, respectively.
AAVs make ideal gene therapy vectors due to their small size, genetic simplicity, and low immunogenicity. However, several limitations are hindering the widespread use of AAVs as a therapeutic modality.
Current challenges include:
These limitations necessitate the administration of large numbers
of viral particles to ensure enough target cells are transduced. But using such large doses has raised safety concerns following reports of serious adverse events occurring in several treated patients in clinical trials, including the deaths of several patients.2,3
One way to address these shortcomings is to re-evolve or re-engineer AAVs to create novel viral vectors with enhanced specificity, immune escape, and safety profiles. For example, several strategies are being explored to re-engineer the viral capsid to overcome tropism limitations. AAV capsid engineering can broadly be divided into two approaches: directed evolution and rational design.
Directed evolution strategies are based on two fundamental steps of natural evolution: creating a gene pool and selection of the fittest. The first step involves generating capsid libraries that introduce diversity into the viral coat protein. This is followed by large-scale screening and selection of variants with desired properties (e.g., tropism) in cell culture and/or animal models.
An alternative approach is rational design, which requires a priori knowledge of AAV sequences, structure, and interactions. This knowledge can be used to modulate, enhance, and optimize vector performance. For this approach, the capsid structure is directly altered; for example by point mutations, targeting ligand insertions, or chemical biology methods.
Both directed evolution and rational design are promising strategies for improving the efficacy of AAVs for clinical application. Of all the capsid properties that could be improved, increasing tissue-specific transduction would mean that a higher proportion of the administered capsids deliver their payloads to the intended cells, reducing the dose needed for effective treatment. This is key to improving the safety profile of AAV-based therapeutics. Capsid engineering is also being utilized to develop vectors that can be used to treat patients with preexisting immunity toward natural AAV serotypes. Biodistribution of barcoded AAV vectors in vivo is the final step for identification of a lead vector with improved delivery or expression properties.
At PerkinElmer, we are working with leading collaboration partners in the field to ensure you have access to the latest research, technology, and expertise when designing your ideal vector vehicles to deliver your target gene of interest.
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