Background: Adeno-associated Virus (AAV) vectors are the most promising vehicles for
therapeutic gene delivery to the retina. To develop a practical gene delivery tool, achieving high AAV
transduction efficiency in specific cell types is often required. AAV-mediated targeted expression in
retinal bipolar cells is needed in certain applications such as optogenetic therapy, however, the transduction
efficiency driven by endogenous cell-specific promoters is usually low. Methods that can improve
AAV transduction efficiency in bipolar cells need to be developed.
Objective: The study aimed to examine the effect of proteasome inhibitors on AAV-mediated transduction
efficiency in retinal bipolar cells.
Methods: Quantitative analysis of fluorescent reporter protein expression was performed to assess the
effect of two proteasome inhibitors, doxorubicin and MG132, on AAV-mediated transduction efficiency
in retinal bipolar cells in mice.
Results: Our results showed that doxorubicin can increase the AAV transduction efficiency in retinal
bipolar cells in a dose-dependent manner. We also observed doxorubicin-mediated cytotoxicity in retinal
neurons, but the cytotoxicity could be mitigated by the coapplication of dexrazoxane. Three
months after the coapplication of doxorubicin (300 μM) and dexrazoxane, the AAV transduction efficiency
in retinal bipolar cells increased by 33.8% and no cytotoxicity was observed in all the layers of
Conclusion: Doxorubicin could enhance the AAV transduction efficiency in retinal bipolar cells in
vivo. The potential long-term cytotoxicity caused by doxorubicin to retinal neurons could be partially
mitigated by dexrazoxane. The coapplication of doxorubicin and dexrazoxane may serve as a potential
adjuvant regimen for improving AAV transduction efficiency in retinal bipolar cells.