Streamlining Viral Gene Therapy Development

Genetics contributes to the development and progression of almost all human diseases from rare genetic disorders to cancer.¹ Clinicians often prescribe drugs to help patients afflicted with genetic diseases, but many products treat their symptoms without addressing the underlying cause. However, that changed with the development of gene therapy. These treatments correct genetic errors in the patient’s cells in vivo using several strategies, such as replacing faulty genes with functional copies, altering gene expression, and editing mutations in the genome.² Since August 2023, the US Food and Drug Administration (FDA) has approved eight gene therapies with many more in the preclinical and clinical development pipeline.³

Designing Optimal Gene Therapies

To generate successful gene therapies that are capable of delivering nucleic acids to specific cells and tissues, scientists must carefully design their products. They can employ either recombinant viruses, such as adenovirus, adeno-associated virus (AAV), retrovirus, or lentivirus, or non-viral platforms, such as lipid nanoparticles, to transport the chosen plasmids, cDNA, or RNA molecules.² However, not all vectors have equivalent properties, with some possessing higher packaging capacities, delivery efficiencies, tissue specificities, and immunogenicity.⁴ For instance, different AAV serotypes are better able to transduce particular tissue types, such as AAV12 into salivary gland cells.⁵ Additionally, different combinations of payloads and vectors will alter aspects of the gene therapy product’s functionality including biodistribution, transgene expression, dose required for treatment, toxicity, and biological effect. 

In hopes of rapidly generating a gene therapy, many researchers attempt to progress from in vitro testing to in vivo studies as quickly as possible. But the high costs associated with maintaining animal models preclude scientists from testing multiple versions of their product. Without optimizing the gene therapy in earlier stages, this approach often slows or halts the therapy’s development, costing both time and money. Moreover, scientists often underestimate the difficulty in swiftly, reliably, and safely manufacturing high-quality therapies in the necessary quantities required for each stage of the development pipeline. Researchers have developed several strategies to overcome the limitations in their existing workflows. They can perform additional in vitro or ex vivo testing to help reduce the risks because these model systems are more cost-efficient than animal models. This allows scientists to screen different payload and packaging combinations and ensure that they have generated an optimal gene therapy.

Helping Scientists Develop the Next Gene Therapies

To ensure they have the materials required for each testing phase, researchers can also rely on off-the-shelf plasmid and viral vector solutions, such as those offered by Charles River as a part of their gene therapy products and services portfolio. The company manufactures research-, high quality-, and good manufacturing practice-grade AAV and lentivirus viral vector (LVV) packaging plasmids to provide scientists with a comprehensive concept to cure portfolio ready for all stages of therapy development. Charles River also supplies AAV and LVV reference materials expressing tags and fluorophore reporters to use as controls for in vitro and in vivo assays. In addition to off-the-shelf products, the company provides researchers with options for custom AAV and LVV plasmids designed and manufactured with their choice of promoters, tags, and reporters. This allows them to tailor the construct to suit their specific product needs. Scientists can also employ the viral vector packaging service, which supplies ready-to-use recombinant AAV and lentiviral particles for projects of any size, such as small-scale in vitro testing, large-scale animal studies, and late-stage clinical trials. Charles River partners with scientists to provide them with the products, services, expertise, and support that they need to produce the next groundbreaking gene therapies.

References

1. Jackson M, et al. The genetic basis of disease. Essays Biochem. 2018;62(5):643-723.
2.  Ay C, Reinisch A. Gene therapy: Principles, challenges and use in clinical practice. Wien Klin Wochenschr. 2024.
3. Henderson ML, et al. Gene therapy for genetic syndromes: Understanding the current state to guide future care. BioTech. 2024;13(1):1.
4. Ghosh S, et al. Viral vector systems for gene therapy: A comprehensive literature review of progress and biosafety challenges. Appl Biosaf. 2020;25(1):7-18.
5. Pupo A, et al. AAV vectors: The Rubik’s cube of human gene therapy. Mol Ther. 2022;30(12):3515-3541.