The first gene therapy clinical trials were initiated more than two decades ago thanks
to the previous development of viral vectors that allow high efficiency gene transfer
into mammalian cells. Since then the application of viral gene transfer has been a
successful treatment option for a variety of diseases. Hematopoietic stem cells (HSCs)
represent the most frequently targeted cell population for the treatment of severe
monogenic diseases as their gene therapeutic correction is a valid alternative to
conventional HSC transplantation when a compatible donor is not available. Indeed,
viral gene transfer was successfully applied in HSC-based ex vivo gene therapy of
the blood and immune systems, albeit several studies have exposed serious adverse
effects that were caused by the therapeutic vector induced inappropriate activation
of proto-oncogenes. After these failures, researchers have developed new types of
randomly integrating vectors that have proven safer in preclinical studies, which
is consistent with interim reports of clinical trials also foreshadowing that they
potentially have an improved safety profile. This review focuses on new and clinically
relevant DNA transposon-based gene delivery vectors, and compares their properties
with those of the old and new generation viral vectors.