CRISPR-Cas9 gene editing for sickle cell disease and β-thalassemia
| Autor: | Angela Yen, Damiano Rondelli, la Fuente Josu de, Amanda M. Li, Jennifer Domm, Montalembert Mariane de, Tony W. Ho, Donna A. Wall, Brenda K. Eustace, Juergen Foell, Sujit Sheth, Haydar Frangoul, Rupert Handgretinger, Akshay Sharma, Sandeep Soni, Antonis Kattamis, Andrew Kernytsky, Franco Locatelli, Stephan A. Grupp, M. Domenica Cappellini, Julie A. Lekstrom-Himes, Selim Corbacioglu, David Altshuler, Markus Y. Mapara, Yi-Shan Chen, Martin H. Steinberg |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities Anemia Thalassemia Cell CD34 Disease Biology 030204 cardiovascular system & hematology 03 medical and health sciences 0302 clinical medicine Genome editing hemic and lymphatic diseases Fetal hemoglobin medicine CRISPR 030212 general & internal medicine Progenitor cell Enhancer Genetics business.industry Obstetrics and Gynecology General Medicine medicine.disease Haematopoiesis medicine.anatomical_structure Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA Immunology Bone marrow CRISPR-Cas9 business |
| Popis: | Transfusion-dependent β-thalassemia (TDT) and sickle cell disease (SCD) are severe monogenic diseases with severe and potentially life-threatening manifestations. BCL11A is a transcription factor that represses γ-globin expression and fetal hemoglobin in erythroid cells. We performed electroporation of CD34+ hematopoietic stem and progenitor cells obtained from healthy donors, with CRISPR-Cas9 targeting the BCL11A erythroid-specific enhancer. Approximately 80% of the alleles at this locus were modified, with no evidence of off-target editing. After undergoing myeloablation, two patients - one with TDT and the other with SCD - received autologous CD34+ cells edited with CRISPR-Cas9 targeting the same BCL11A enhancer. More than a year later, both patients had high levels of allelic editing in bone marrow and blood, increases in fetal hemoglobin that were distributed pancellularly, transfusion independence, and (in the patient with SCD) elimination of vaso-occlusive episodes. (Funded by CRISPR Therapeutics and Vertex Pharmaceuticals; ClinicalTrials.gov numbers, NCT03655678 for CLIMB THAL-111 and NCT03745287 for CLIMB SCD-121.). |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|