고려대 의대 BK21 특별 세미나
Using clinical genetics to engineer a selective advantage into genome-edited RBCs
Kyle Cromer, PhD
Assistant Professor, Surgery
School of Medicine
University of California, San Francisco, USA
Due to disease prevalence and the amenability of hematopoietic stem cells (HSCs) to ex vivo culture and transplantation, multiple genome editing trials have been initiated to treat the hemoglobinopathies. However, the greatest barrier to a cure is achieving sufficient red blood cell (RBC) chimerism in the bloodstream following transplantation of modified HSCs. While edited HSCs yield genome-corrected cells of all lineages (T cells, B cells, macrophages, etc.), the only cell type of clinical relevance to the hemoglobinopathies is the RBC. Therefore, technology to bias edited HSCs toward the erythroid lineage would allow low HSC chimerism in the BM to yield high levels of RBC chimerism in the bloodstream. Taking a cue from clinical genetics, we know that truncations in the erythropoietin receptor (EPOR) lead to benign erythrocytosis?yielding non-pathogenic hyper-production of RBCs. Using genome editing we have replicated these mutations which dramatically bias HSCs toward the erythroid lineage in vitro. Based on robust preliminary results, our central hypothesis is that we can link EPOR truncation events with current hemoglobinopathy correction strategies to increase RBC chimerism in the bloodstream from a small population of engrafted HSCs. We will first vet these strategies using patient-derived HSCs in vitro, and then demonstrate erythroid bias of edited HSCs in vivo following transplantation into immunodeficient mouse models. We believe this tEPOR expression strategy could be immediately combined with current clinical efforts to address one of the greatest bottlenecks for effective treatment of the hemoglobinopathies?producing sufficient corrected RBCs in vivo. More broadly, this work will present a proof-of-concept for how genome editing can be used to introduce non-pathogenic clinical variants to bias stem cells toward production of clinically relevant cell types. We believe this could result in a significant paradigm shift in how the problem of low editing frequency and engraftment is addressed in a wide range of cell-based therapies for an array of different diseases.
- 일 시: 2022.10.18. (화요일) 오전 11시~
- 줌 링크:
Meeting ID: 966 1477 0649
Passcode: v0QW8UkBn1
- 문 의: 최정민 교수님 (jungminchoi@korea.ac.kr),
김경미 교수님(kim0912@korea.ac.kr)