Adeno-Associated Virus Vectors and Stem Cells: Friends or Foes?

Abstract

The infusion of healthy stem cells into a patient-termed "stem-cell therapy"-has shown great promise for the treatment of genetic and non-genetic diseases, including mucopolysaccharidosis type 1, Parkinson's disease, multiple sclerosis, numerous immunodeficiency disorders, and aplastic anemia. Stem cells for cell therapy can be collected from the patient (autologous) or collected from another "healthy" individual (allogeneic). The use of allogenic stem cells is accompanied with the potentially fatal risk that the transplanted donor T cells will reject the patient's cells-a process termed "graft-versus-host disease." Therefore, the use of autologous stem cells is preferred, at least from the immunological perspective. However, an obvious drawback is that inherently as "self," they contain the disease mutation. As such, autologous cells for use in cell therapies often require genetic "correction" (i.e., gene addition or editing) prior to cell infusion and therefore the requirement for some form of nucleic acid delivery, which sets the stage for the AAV controversy discussed herein. Despite being the most clinically applied gene delivery context to date, unlike other more concerning integrating and non-integrating vectors such as retroviruses and adenovirus, those based on adeno-associated virus (AAV) have not been employed in the clinic. Furthermore, published data regarding AAV vector transduction of stem cells are inconsistent in regards to vector transduction efficiency, while the pendulum swings far in the other direction with demonstrations of AAV vector-induced toxicity in undifferentiated cells. The variation present in the literature examining the transduction efficiency of AAV vectors in stem cells may be due to numerous factors, including inconsistencies in stem-cell collection, cell culture, vector preparation, and/or transduction conditions. This review summarizes the controversy surrounding AAV vector transduction of stem cells, hopefully setting the stage for future elucidation and eventual therapeutic applications.

Keywords: AAV vectors; ITR; gene therapy; stem cell; stem cell therapy.

Figure 1.

Select putative transcription factor binding sites of the adeno-associated virus serotype 2 (AAV2) inverted terminal repeat (ITR). The consensus sequence of the AAV2 ITR was analyzed using the mfold web server for predicted folding structures and ALGGEN PROMO^, for putative transcription factor binding sites. A representative selection of putative transcription factor binding sites is indicated on the sole predicted structure with line overlays (shown above). The Rep binding element (RBE) and the RBE′ are delineated with boxes, and the terminal resolution site (trs) is indicated with an arrow. Color images available online at www.liebertpub.com/hum