Blood is essential for oxygen transport, wound healing, and defence against pathogens. Short-lived mature blood cells are constantly replenished by hematopoietic stem cells (HSCs) throughout life. The production or function of blood cells is impaired in a plethora of rare genetic disorders, such as hereditary anemias (caused by insufficient numbers of functional red blood cells (RBCs)), bone marrow failure syndromes and immune deficiencies. Therapeutic options are limited and allogeneic HSC transplantation is currently the only cure. Unfortunately, for many patients there is no suitable donor available. Incomplete knowledge of disease mechanisms, partly due to scarce availability of patient-derived HSCs, impedes the development of new therapies. TRACER will focus on inherited monogenic anemias. The physiological and molecular mechanisms underlying these disorders are still incompletely understood. Our multidisciplinary team aims to employ iPSCs to: 1) study disease mechanisms, 2) generate engraftable HSCs and transfusable RBCs and 3) develop curative therapies. We will focus on mechanisms involved in congenital anemias, and on the production of RBCs and HSCs from gene-corrected iPSCs. Advanced single-cell analysis methods will delineate how HSCs are generated from iPSCs. Bioreactor technology will be applied to expand and differentiate iPSCs under controlled conditions. To ascertain maximal benefit, we will examine the ethical, legal and societal impact of these new technologies on patients, clinicians, policymakers, regulatory bodies, pharmaceutical enterprises and the general public.
The overall aim of the TRACER is to harness the potential of iPSCs for regeneration of the erythroid system. Our focus is on SCA and DBA, two rare monogenic anemias where innovative patient-tailored curative treatments are desperately needed. In TRACER, we aim to:
- Develop iPSC-based differentiation protocols to understand and correct rare anemias molecularly.
• Regenerate the erythroid system by developing protocols to produce iPSC-derived HSCs and RBCs.