Disease-associated genomic DNA sequence in hematopoietic stem cells

Disease-associated genomic DNA sequence in hematopoietic stem cells refers to specific genomic loci within hematopoietic stem cells (HSCs) that are targeted for therapeutic modification, primarily through gene-editing technologies such as CRISPR/Cas9 and zinc finger nucleases (ZFNs). This target represents the physical DNA sequence being altered to either correct a disease-causing mutation or modulate the expression of genes involved in hematological and immunological disorders. Common examples include the BCL11A erythroid-specific enhancer, which is edited to induce fetal hemoglobin (HbF) production in patients with sickle cell disease or beta-thalassemia, and the CCR5 gene, which is modified to provide resistance to HIV infection. Because HSCs are self-renewing and multipotent, modifications at these genomic sequences are permanent and inherited by all progeny cells, including red blood cells and immune cells. This approach offers the potential for a one-time, curative treatment for chronic genetic conditions. Therapeutic strategies targeting these sequences typically involve ex vivo modification of patient-derived CD34+ cells followed by autologous transplantation. Key challenges include ensuring high editing efficiency and minimizing off-target effects that could lead to genotoxicity or clonal hematopoiesis.

Other names

BCL11A geneBCL11A erythroid-specific enhancerHBB geneHBG1/HBG2 promoterCCR5 geneGenomic DNA sequenceTargeted genomic sequence

Gene editing of specific genomic sequences to modulate gene expression or correct mutations.