Gene therapy of hematopoietic stem cells

Summary

An estimated 24 million people in the European Union alone are affected by an inherited disorder based on a genetic defect. In humans, approximately 7,000 inherited diseases have been identified; in around 1/3 the genetic defect has been mapped and the function of the affected gene elucidated. Human suffering as well as health care costs are immense, and therefore the development of future curative therapy is a humanitarian, medical, societal, and economic necessity.

In patient numbers, the inherited diseases are most frequent in disorders of the blood cell producing system. This provides the rationale for a focus on hematopoietic stem cells as a prime target of gene therapy, solidly rooted in 40 years of experience with the clinical application of HSC transplantation for a variety of acquired and inherited disorders. In those disorders based on a monogenic defect, ex vivo gene correction of the patient’s hematopoietic stem cells and transplantation of those cells is a realistic treatment concept. Due to the specific properties of the progeny of hematopoietic stem cells, curative approaches for disorders in other organ systems also turn out to be accessible to hematopoietic stem cell gene therapy, including disorders that affect the brain. In this overview the results of a European consortium’s (www.gene-therapy.eu) translational research project – in which leading centers collaborated to prepare for the effective and safe gene therapy of selected example diseases that included severe combined immune deficiencies, red cell disorders, and lysosomal enzyme deficiencies – are presented. The research also required an in-depth analysis of the interaction of gammaretroviral and lentiviral vectors with stem cell genome expression levels, revealing new insights in hematopoietic stem cell genomics.

Keywords

inherited diseases, hematopoietic stem cell transplantation, HSCT, gene therapy