Gene therapies are emerging as promising treatments for previously untreatable genetic disorders, with adeno-associated viruses (AAVs) being the preferred vector for gene delivery. However, AAV-based gene therapies face challenges in production, including cost, complexity, and scalability. With the gene therapy market projected to grow significantly, drug developers are seeking platforms that streamline AAV production. Key factors include ensuring flexibility to accommodate different therapies, minimizing risks by understanding the entire process, and scaling production as projects progress. A well-designed AAV platform can enhance efficiency, quality, and regulatory compliance, ensuring safe delivery of therapies to patients.
October 18, 2024
Gene therapies have emerged rapidly as promising treatment options for genetic disorders that previously were considered untreatable, such as cancers, rare diseases, and neurological disorders (1). Adenoassociated viruses (AAVs) are the preferred vector for gene delivery because they can be cultured to relatively high titers and show good long-term transgene expression in vivo (2, 3). However, manufacturing AAV-based gene therapies is a complex process demanding cost-efficiency, flexibility, and speed in all aspects of production.
Below, I delve into the increasing necessity for carefully designed development platforms to deliver cutting-edge AAV therapies efficiently and safely to patients.
Growing Reliance on AAV-Production Platforms
The gene-therapy market is growing rapidly, with more than 2000 gene therapies (including genetically modified cell therapies) currently under development (1). With the biopharmaceutical industry increasingly recognizing the potential of gene therapies, the global gene-therapy market is predicted to reach a value of US$23.9 billion by 2028 (4).
Despite the promise of effective, innovative gene therapies, their inaccessibility and high costs pose significant challenges. Lenmeldy (atidarsagene autotemcel), the world’s most expensive gene therapy, offers hope for metachromatic leukodystrophy patients but comes with a price tag of about $4.25 million (5). Successfully providing gene therapies to patients relies on drug developers and manufacturers navigating the intricate balance of upholding quality standards while optimizing cost-effectiveness and expediting timelines. That challenge has prompted AAV-therapy developers to seek collaborations with contract development and manufacturing organizations (CDMOs) that offer robust platforms tailored to meet such needs.
Platform Approaches To Overcome Complexity
Despite the rapid expansion of the gene-therapy sector since the first approved therapy in 1990, drug companies have yet to establish a standard procedure for gene-therapy development and manufacturing (6). This can be attributed to the many complexities associated with AAV production, which differ across products and processes. AAV manufacturing involves many steps, encompassing plasmid production, transient transfection/infection, upstream production, downstream processing, and fill–finish. The choice of upstream process and associated conditions depends on several factors such as the virus, host cell line, transfection reagents, and culture medium to be used. Decisions made during upstream production have a cascading effect on the selection of downstream processing methods. Adding to the complexity of AAV production, each of those processes requires optimization to ensure quality, safety, scalability, and cost-effectiveness. Therefore, a comprehensive understanding of how decisions in each stage affect subsequent processes and future scale-up is crucial.
Biotechnology companies with AAV programs also face pressure to accelerate manufacturing timelines. Such demand is driven not only by the need to demonstrate potential return on investment (RoI) to investors, but also by the desire to assist patients.
With pressure to accelerate the complex production of AAV therapies, many developers and manufacturers are looking for a robust, established platform to simplify the process. By developing an AAV platform, developers can streamline production while lowering costs, reducing complexity, and forging a clear path to clinical phases and commercialization. However, designing and developing an AAV platform is no easy task and requires strategies that ensure built-in flexibility and scalability while minimizing risk.
Minimizing Risks: Although biotechnology companies with AAV programs face pressure to accelerate delivery, the inherent complexity of AAV-therapy development and manufacturing poses significant risks. Poor decision-making can cause costly delays to critical milestones.
A comprehensive approach to developing AAV platforms can enable identification of potential risks early, leading to proactive solutions. To attain a holistic viewpoint, developers and manufacturers must possess a profound understanding of every step in the process while remaining adaptable to necessary adjustments. Developers and manufacturers with substantial experience in supporting various virotherapy projects will understand the unique needs of different drug modalities. Their intimate knowledge will help them to anticipate how such needs might evolve as projects progress toward commercialization and to account for those changes when developing the AAV platform.
Ensuring Flexibility: Candidate gene therapies are diverse, each one targeting a specific disease with a distinct, highly engineered viral vector of a specific serotype. Achieving commercial viability will require a flexible platform that can accommodate such diversity. Developers must leverage the most suitable technology, cell line, and process to optimize yield, quality, safety, and efficacy for each therapy. With flexibility built into the AAV platform, developers can tailor their approaches to each project’s requirements, enhancing the success of AAV-based therapies.
Designing AAV platforms with flexibility in mind is also critical to ensuring consistent regulatory compliance. The gene-therapy sector has experienced rapid advancements in methodologies and technologies, allowing developers to attain higher viral-vector yields, enhanced quality, and efficient project scaling. Consequently, regulators have had to adapt their guidelines. To ensure a continuous supply of advanced therapies, AAV-production platforms must be able to incorporate new technologies and advancements while maintaining compliance in a changing regulatory landscape.
Expertise in a broad spectrum of viral vectors is essential for developers and manufacturers to ensure platform flexibility. In-depth knowledge and understanding of each project’s complexities and requirements can help to identify potential risks during the process of developing AAV-based therapies. Producers can draw on their past experiences to find and address potential risks, leading to tailored, effective solutions.
Delivering Scalability: As AAV projects advance from preclinical to clinical phases and eventually commercialization, production needs will expand, with higher volumes required at each stage. Consequently, manufacturing processes must be adaptable and robust enough to ensure consistent product quality at each scale-up phase. Establishing an AAV platform requires developers and manufacturers to adopt a comprehensive, systematic approach, ensuring careful consideration of how project needs might change over time. A program should begin with small-scale screening of cell lines, reagents, and methods to identify optimal conditions. Developers and manufacturers then can use design of experiments (DoE) methodologies to optimize those conditions with the aim of maximizing yield and quality while minimizing costs. Once the process performs consistently in benchtop bioreactors, the project can advance to pilot-scale production.
Looking to the Future
As reliance on AAVs for gene therapies grows, needs also increase for carefully designed development platforms that can deliver AAV therapies to patients efficiently and safely. To do so, developers and manufacturers must navigate the complexity, cost, and scalability of AAV manufacturing. Robust platform approaches will play a critical role in overcoming complexity, minimizing risk, and ensuring flexibility in AAV development and manufacturing to continue delivering innovative therapies to the patients who need them.
References
1 Barrett D, et al. Gene, Cell, + RNA Therapy Landscape Report: Q4 2023 Quarterly Data Report. American Society of Gene + Cell Therapy, 2023; https://www.asgct.org/global/documents/asgct-citeline-q4-2023-report.aspx.
2 Wang D, Tai PWL, Gao G. Adeno-Associated Virus Vector as a Platform for Gene Therapy Delivery. Nat. Rev. Drug Discov. 18(5) 2019: 358–378; https://doi.org/10.1038/s41573-019-0012-9.
3 Lansford R. Engineering Viruses for CNS Studies. Encyclopedia of Neuroscience. Squire LR, Ed. Academic Press: Cambridge, MA, 2009: 1059–1068.
4 Gene Therapy Market Size by Type, Vector, Non-Viral, Therapeutic Area, Delivery Method, RoA, & Region — Global Forecast to 2028. MarketsandMarkets Research, 2023; https://www.marketsandmarkets.com/Market-Reports/gene-therapy-market-122857962.html.
5 Package Insert — Lenmeldy. US Food and Drug Administration: Silver Spring, MD, 15 April 2024; https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/lenmeldy.
6 Scheller EL, Krebsbach PH. Gene Therapy: Design and Prospects for Craniofacial Regeneration. J. Dent. Res. 88(7) 2009: 585–596; https://doi.org/10.1177/002203
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Corresponding author Xiaojun Liu is director of AAV process development at ReciBioPharm; 650 Pleasant Street, Watertown, MA 02472; [email protected].
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