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Isolation of Next-Generation Gene Therapy Vectors through Engineering, Barcoding, and Screening of Adeno-Associated Virus AAV Capsid Variants
Published on: October 18, 2022
Development of Gene Therapy Vectors: Remaining Challenges
Vibhor Gupta1, Sílvia P Lourenço1, Ismael J Hidalgo1
1Absorption Systems, LLC, Exton, PA 19341, USA.
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.
Insights
Gene therapy, using viral vectors like adeno-associated viruses (AAVs), shows promise for treating genetic disorders. However, challenges remain in AAV product development, including assessing neutralizing antibodies and ensuring in-vitro bio potency for clinical success.
Area of Science:
- Biotechnology
- Gene Therapy
- Viral Vectors
Background:
- The approval of Luxturna® marks a significant advancement in gene therapy for inherited blindness, following early setbacks in the field.
- Gene therapy strategies involve gene replacement or editing to restore protein function, utilizing various viral and non-viral delivery vectors.
- Recombinant adeno-associated viruses (AAVs) are favored delivery vehicles due to their safety, specificity, and long-term stability, despite challenges.
Purpose of the Study:
- To highlight critical aspects of adeno-associated virus (AAV) product development for gene therapy.
- To discuss the ongoing challenges in AAV pre-clinical and clinical development.
- To emphasize the importance of cell-based assays for AAV development.
Main Methods:
- Review of current gene therapy approaches and vector technologies.
- Analysis of challenges in AAV product development and regulatory pathways.
- Discussion of cell-based assays for evaluating neutralizing antibodies and in-vitro bio potency.
Main Results:
- Non-viral vectors offer alternatives to viral vectors by mitigating immunogenicity and neutralizing antibody issues.
- AAVs have demonstrated early success in gene therapy delivery, but face hurdles in development and approval.
- Engineering of AAV serotypes necessitates robust assays for assessing seroprevalence and bio potency.
Conclusions:
- Addressing challenges in AAV development, including immunogenicity and potency assays, is crucial for advancing gene therapy.
- Continued research into AAV vectors and associated assays will facilitate the successful translation of gene therapies into clinical practice.
- Optimizing AAV delivery systems and characterization methods is key to overcoming current limitations in gene therapy product development.
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