Small molecule inhibition of SUMOylation increases expression from AAV vectors both during and after initial transduction in mice.

Adeno-associated virus-based vector (AAV)-based gene therapy has been used to treat thousands of patients, but a limitation can be inefficient transgene expression from AAV vectors. AAV transduction can be affected by the small ubiquitin-like modifier (SUMO) system, in which SUMO proteins are attached to proteins after translation, thereby modulating their function and stability. However, to date, practical modulators of SUMOylation to increase AAV vector transgene expression have not been available. Here we demonstrate that small molecule inhibitors of SUMOylation can boost expression from AAV vectors. Treatment with the SUMOylation inhibitor TAK-981 sharply increased AAV transgene expression in transformed human cells, in primary human cells, and in mice. Increased transgene expression in vitro and in vivo was associated with increased mRNA levels per vector DNA template. Treatment of mice with TAK-981 during AAV delivery increased AAV transgene expression; in addition, TAK-981 could boost transgene expression when introduced at long times after initial AAV vector transduction, regardless of whether mice had been exposed to TAK-981 previously. Modulators of SUMOylation are currently in clinical trials in human patients and, thus, may soon represent a viable strategy for boosting AAV transgene expression to improve human gene therapy outcomes.