NM_000518.5(HBB):c.118C>T (p.Gln40Ter)

For HBB c.118C>T (p.Gln40Ter), a pathogenic nonsense variant that produces no functional adult beta-globin, exagamglogene autotemcel (Casgevy, exa-cel, Vertex/CRISPR Therapeutics) represents the first CRISPR-based gene-editing therapy approved for a genetic disease. Rather than correcting the HBB mutation directly, Casgevy edits the BCL11A erythroid-specific enhancer in autologous CD34+ hematopoietic stem cells ex vivo, disrupting the transcriptional repressor that silences fetal hemoglobin (HbF) expression in adult erythroid cells. This reactivates gamma-globin production and HbF synthesis, compensating for the absent beta-globin. Casgevy received FDA and EMA approval in late 2023 for transfusion-dependent beta-thalassemia (TDT) and sickle cell disease.

The CLIMB THAL-111 pivotal trial demonstrated that 91% of TDT patients treated with exa-cel achieved transfusion independence for at least 12 consecutive months (primary endpoint), with sustained total hemoglobin levels >11 g/dL driven by HbF levels of 40% or higher. The editing efficiency at the BCL11A enhancer target site exceeded 90% in infused CD34+ cells. Follow-up data at 2+ years showed durable transfusion independence. The biological rationale is validated by natural human genetics: individuals with hereditary persistence of fetal hemoglobin (HPFH) who carry beta-thalassemia mutations have a mild or asymptomatic phenotype because HbF compensates for the beta-globin deficit. Disrupting BCL11A function specifically in erythroid cells (via the GATA1-binding erythroid enhancer) preserves BCL11A expression in other lineages where it is essential (B lymphocytes). For p.Gln40Ter, which produces no beta-globin at all, the HbF compensation strategy is particularly appropriate because there is no residual beta-chain to participate in hemoglobin assembly.

Casgevy requires myeloablative conditioning with busulfan to clear existing bone marrow and enable engraftment of edited HSPCs, carrying risks of veno-occlusive disease, prolonged cytopenias, infection, and infertility. The manufacturing process (leukapheresis, CD34+ selection, electroporation with CRISPR RNP, quality testing, cryopreservation) takes approximately 4-6 months, during which patients remain transfusion-dependent. Off-target editing at the BCL11A locus has been characterized extensively; no clinically significant off-target events have been identified, but long-term mutagenesis monitoring is ongoing. The therapy is a one-time treatment but at extremely high cost ($2.2 million list price in the US). Access in low-and-middle-income countries where beta-thalassemia prevalence is highest (Mediterranean, South/Southeast Asia, Middle East) remains a major equity concern. Alternative approaches include lovotibeglogene autotemcel (Zynteglo, lentiviral beta-globin gene addition, also approved) which adds a functional beta-globin gene rather than reactivating HbF.