Using inducible signaling receptors for in vivo fate determination of hematopoietic stem cells to erythroid-specific lineages

Over 7,000 disease-causing mutations have been identified to date, with this number increasing as more are identified. Cell and gene therapies (CGTs) represent a promising therapeutic avenue for generating definitive cures for a myriad of genetic and congenital disorders. However, CGTs are classically limited by editing and delivering efficiencies. This is especially true within the context of hematopoietic stem and progenitor cell (HSPC) gene therapy, where the degree of phenotypic effect is directly related to the degree of differentiation into disease-relevant lineages and the quantitative ability of the engineered cell and its progeny to engraft.
This study presents a set of first-in-class chimeric, synthetic receptors that support HSPC output down towards the erythroid lineage via a non-immunogenic, non-toxic small molecule.
Through functional assays and quantifying edited allele frequency changes during differentiation, this study has demonstrated these synthetic receptors— termed “erythroid cell drives”— that mimic the native erythropoietin/erythropoietin receptor signaling cascade with high fidelity and sensitivity. Additionally, these erythroid cell drives are demonstrated to be erythropoietin independent, dose responsive, and tunable via expression from different loci and promoters.
In sum, erythroid cell drives represent a powerful new tool for clinicians with which to alter the cellular dynamics of CGTs post transplantation and boost the production of clinically relevant red blood cells. The work demonstrated in this study has the potential to dramatically improve the efficacies of existing CGTs as well as offer a new tool by which to better understand stem cell biology.