Human Hematopoietic Stem/Progenitor cell trafficking and clonal tracking

Hematopoietic Stem and Progenitor cell gene therapy is one of the approaches used to correct genetic disorders based on infusion of gene-modified hematopoietic stem cells collected from bone marrow or mobilized peripheral blood of patients and engineered ex vivo with viral vectors. This strategy has proven its efficacy in the treatment of some genetic diseases including primary immunodeficiencies (such as Wiskott-Aldrich Syndrome, Adenosine deaminase deficiency), in which affected patients display an impaired immune system and failure to clear viral and bacterial infections, as well as neurodegenerative disorders (such as Metachromatic leukodystrophy) characterized by progressive loss of cognitive and motor activities. Initial promising data have been obtained for lysosomal storage disorders with bone involvement such as mucopolysaccharidosis type I. Few circulating HSPC can be also found in peripheral blood but their role and the molecular mechanisms responsible for their re-circulation is poorly understood. Our project has the main goal to study the properties, dynamics and biology of hematopoietic stem cells at steady-state and after infusion into the patients. In particular we are dissecting: a) the molecular mechanisms responsible for physiological trafficking and drug-induced mobilization; b) the functional properties of circulating hematopoietic stem cells, with the aim of exploiting them as new source for hematopoietic stem cell gene therapy; c) the characteristics of the engrafted hematopoietic stem cells long term (more than 8 years) from the injection. To these aims, we combine multiple innovative approaches including tracking each single hematopoietic stem cell and its progeny directly into the patients thanks to the concept that upon gene-correction, each stem cell became molecularly marked by distinct site, where the therapeutic vector integrated into the DNA of the patients’ cells.The information generated from our studies will allow to increase our knowledge on the hematopoietic stem cell biology ultimately leading to improved gene therapy strategies and to extend this type of treatment to other diseases.