Gene of the Month – January: BCL11A
Sickle cell disease and beta thalassemia are blood disorders with defective hemoglobin formation due to mutations in the HBB gene, encoding a subunit of adult hemoglobin. They are associated with severe manifestations including repeated strong pain and can lead to a reduced life expectancy. BCL11A is a transcription factor that represses the synthesis of gamma globin, a component of fetal hemoglobin. While the production of fetal hemoglobin normally decreases after birth, the study investigators designed their approach of knocking out BCL11A to reactivate its production.
In the clinical phase I/II study sponsored by pharmaceutical companies CRISPR Therapeutics and Vertex Pharmaceuticals, the researchers harvested hematopoietic stem and precursor cells from their patients and genetically engineered a specific, regulatory enhancer segment of BCL11A. Then they reinfused the cells back into the patients. The same NEJM issue also reports another gene therapy approach targeting BCL11A to treat sickle cell disease. In this second study, researchers used lentiviral vectors and microRNA to block BCL11A production, a strategy which also yielded positive results.
Frangoul H, Altshuler D, Cappellini MD, … Corbacioglu S. CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia. N Engl J Med. 2021 Jan 21;384(3):252-260. doi: 10.1056/NEJMoa2031054.
Esrick EB, Lehmann LE, Biffi A, … Williams DA. Post-Transcriptional Genetic Silencing of BCL11A to Treat Sickle Cell Disease. N Engl J Med. 2021 Jan 21;384(3):205-215. doi: 10.1056/NEJMoa2029392.