Liver-directed gene therapy with helper-dependent adenoviral vectors: current state of the art and future challenges.

Successful liver-directed gene therapy has the potential to revolutionize medicine. Helper-dependent adenoviral vectors (HDAds) are devoid of all viral coding sequences and have shown tremendous potential for liver-direct gene therapy. In small and large animals, hepatic transduction with HDAd has resulted in high level, long-term transgene expression without chronic toxicity in a variety of disease models. Recent advancements in the large-scale manufacture of HDAd have permitted contemplation of clinical application. However, dose-dependent activation of the host innate inflammatory response remains an obstacle for clinical translation. Recent advancements in vector capsid modifications, immune modulation regimes, as well as novel routes of vector administration may yet permit clinical liver-directed gene therapy with HDAd.