Liver transfection, particularly when using viral vectors such as adeno-associated virus (AAV), can result in long-lasting gene expression. This is due to the ability of these vectors to deliver the therapeutic gene into the nuclei of liver cells, where it can continue to be expressed over time. However, the long-term effects and durability of liver transfection are influenced by multiple factors:

1. Immune Response: As we’ve discussed earlier, an immune response to the viral vector or the transgene product can reduce the long-term durability of gene therapy. If immune cells target and destroy cells expressing the transgene, this can lead to a loss of therapeutic benefit over time.
2. Cell Turnover: The liver has a high rate of cell turnover, with hepatocytes being replaced approximately every 200-300 days. This can potentially lead to a loss of transgene expression over time, particularly for non-integrating vectors which do not incorporate their genetic material into the host cell’s genome.
3. Vector Persistence: Non-integrating vectors like AAV persist in the nucleus as episomes (extrachromosomal circular DNA). While these episomes can be stable for many years, they may eventually be lost over time, leading to a decline in transgene expression.
4. Vector Toxicity and Side Effects: Long-term vector toxicity and side effects could potentially cause problems. For example, some viral vectors can integrate into the host genome and cause insertional mutagenesis, leading to a risk of cancer. Also, chronic inflammation due to repeated vector administration could lead to long-term liver damage.
5. Disease Progression: In some diseases, the underlying disease progression may continue despite gene therapy, which could impact the long-term outcomes of the therapy.