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Viral Vectors: The Road to Reducing Genotoxicity
Rhiannon M David1, Ann T Doherty2
1Genetic Toxicology, Discovery Safety, AstraZeneca, Cambridge, CB4 0WG, UK rhiannon.david@astrazeneca.com.
Summary
Viral vectors in gene therapy can cause genotoxicity through gene activation, influenced by vector type and patient factors. Developing safer vectors requires tailored approaches, not a one-size-fits-all solution.
Area of Science:
- Gene Therapy
- Molecular Biology
- Oncology
Background:
- Viral vectors are crucial for gene therapy but pose safety risks, notably genotoxicity.
- Genotoxicity often arises from proto-oncogene activation due to vector insertion or transcriptional effects.
- Factors like vector type, integration site, cell type, and patient characteristics influence genotoxic risk.
Purpose of the Study:
- To provide an overview of viral vector-mediated genotoxicity.
- To discuss factors contributing to genotoxicity and strategies for risk reduction.
- To highlight the importance of appropriate testing for insertional mutagenesis.
Main Methods:
- Review of current literature on viral vector genotoxicity.
- Analysis of mechanisms of vector-mediated genotoxicity.
- Examination of strategies to mitigate insertional mutagenesis risks.
Main Results:
- Enhancer-mediated activation of genes is a primary genotoxicity mechanism in trials.
- Vector integration profiles are virus- and cell-specific, affecting genotoxicity.
- Current strategies like SIN vectors and insulators reduce but do not eliminate insertional mutagenesis.
Conclusions:
- A universal approach to vector modification for genotoxicity reduction is not feasible.
- Addressing genotoxicity is critical for advancing gene therapies, including CRISPR-Cas9.
- Tailored strategies and robust testing are essential for safe gene therapy development.
