Several challenges typically confront shRNA-based therapeutics. The most significant challenge is delivery. shRNA is typically delivered through use of a vector, and although they are generally efficient, they pose significant safety concerns. In particular, viral based gene therapy approaches have proved dangerous in past clinical trials. In the first generation of retro viral gene therapy some patients treated with viral vectors for Wiskott–Aldrich syndrome developed acute T-cell leukaemia. This was determined to have been caused by viral vector insertion location. Potential oversaturation of RISC is also a problem. If the shRNA is expressed at levels that are too high the cell might not be able to correctly process the endogenous RNA which could cause significant problems. Another challenge is the possibility that the patient might mount an immune response against the therapy. Finally, there might be off-target effects and the shRNA could silence other unintended genes. In developing successful new shRNA-based therapeutics, all of these challenges must be taken into account.