Common advantages
- Multiple levels of targeting can be achieved through natural or engineered capsids and transcriptional regulation; longer-term expression can be achieved in many terminally differentiated cells.
- Recombinant vectors usually exist in extrachromosomal form and are suitable for in vivo delivery of secreted proteins, enzymes, reporter genes, regulatory elements and partial editing systems.
- Existing clinical experience in the eye, liver, muscle and nervous system provides a mature analysis and risk framework for study design.
Limitations that must be proactively prompted
- Packaging capacity is limited; scAAV capacity is smaller, and dual AAV will introduce co-transduction and recombination efficiency issues.
- Neutralizing antibodies formed from previous exposure may reduce transduction and limit repeated dosing; both capsids and transgenes can trigger innate or adaptive immunity.
- High systemic doses are associated with hepatotoxicity, complement-related events, and thrombotic microangiopathy; DRG pathology is seen in NHP with CSF or systemic administration.
- Duration of expression depends on cell turnover, immune response, promoter silencing and disease context and should not be uniformly committed.
- Mouse results cannot be directly extrapolated to NHPs or humans; receptor differences can create significant species barriers for engineered capsids.
References for this chapter
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