This research line investigates factors that can produce cellular stress in hematopoietic stem and progenitors cells (HSPCs) in protocols for gene therapy (GT) which could impair the engraftment and the functionality of these cells. Gene modification tools for gene therapy, either by gene addition or gene editing, often require manipulation associated to proliferation stress, processes of activation, electroporation, contact with virus particles and transient DNA damage that can alter HSPCs behavior. Some of these factors can generate stress molecules such as NKG2D ligands that can be recognized by the immune system and therefore produce a detrimental effect against HSPCs. If this hypothesis is confirmed, modifications in transduction protocols aimed at avoiding this cellular stress can maximize viability and engraftment and improve the eficacy of GT for genetic hematopoietic diseases. This is especially important when low number of HSPCs are available, such as in FA patients. In addition, the possible immune recognition of corrected, but stressed cells after transduction protocols, will be of particular relevance in non-conditioned patients (as in FA GT) or when chemoradiotherapy may be replaced by others conditioning processes less detrimental for the activity of immune cells.
