Gene therapy has the potential to treat inherited and acquired diseases. Today, viral vectors are the preferred tool for gene delivery. Once a viral victor replaces the viral genome with a therapeutic gene, it strips the virus of its pathogenic and replicative traits. However, an ideal vector should efficiently and reliably deliver a therapeutic gene to cells and have long-term therapeutic expression. Viruses offer all these characteristics. However, the mammalian immune system recognizes these infectious agents and generates an immune response against them.
Immune responses generated against these viral vectors can affect the application and safety of gene therapy. Hence, immunogenicity analysis becomes critical in gene therapy. Immunogenicity testing involves assessing anti-drug antibodies (ADA). Today, researchers have ELISA ADA assay and cell based assay for evaluating unwanted immune responses. Besides, the neutralizing antibody (NAb) assay helps identify the neutralizing capacities of these anti-drug antibodies. However, adequate NAb assay development and validation is crucial for robust ADA analysis. The current article discusses the ADA study in gene therapy.
Evaluating ADA responses to viral vectors
Pharmacokinetic assessments are vital in understanding ADA responses. Hence, ADA PK analysis includes the evaluation of pharmacokinetic properties affected by anti-drug antibodies.
The applicability of a specific viral vector depends on multiple factors such as tropism, target tissues, packaging capacity, genome integration, and propensity for immunotoxicity. Although LV vectors are preferred for ex vivo gene correction, AVV has now emerged as a perfect alternative for in vivo gene transfer. The primary reason for these preferences is its favorable safety profile capacity to transduce tissues and the availability of multiple viral capsids.
Viral factors use their refined evolutionary process to transduce human cells. However, the human immune system has evolved equally to protect itself by eliminating foreign invaders. For the human immune system, specific viral vector components are indistinguishable. Hence, these vectors are subject to similar adaptive and innate immune responses. Innate immune responses identify viruses by recognizing molecular motifs that trigger antiviral immunity.
The envelope protein or capsid has foreign proteins that can act as targets for adaptive immune responses. Additionally, therapeutic transgene drugs with a new antigen may be targeted by cellular and humoral immune responses.
Immune-mediated rejection is one of the significant challenges in human gene therapy. A complete understanding of biological processes underlying these responses focused against transgene products and viral vectors is vital for developing treatment that reduces immune-mediated rejection. Identifying answers to these questions can deliver robust gene therapy treatments.
Decades of research have resulted in the production of robust viral-based vectors for gene therapy. However, immunogenicity reactions against vectors remain a challenge. A complete understanding of immune reactions against transgene products and vectors will improve the design and targeting approach of gene therapy vectors. Such interventions can potentially expand the reach of gene therapy to a broader set of human conditions. For example, steroid drugs in hepatic, ocular, and systemic AAV gene therapy treat anti-virus and inflammation responses. Additionally, CAR-T cell therapy studies have demonstrated that cytokine release syndrome prevention proves beneficial in managing immunotoxicity due to viral vector gene therapy.
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