NM_000518.5(HBB):c.92+5G>C

Exagamglogene autotemcel (Casgevy), the first CRISPR-Cas9-based therapy approved by the FDA (December 2023) and EMA, targets the BCL11A erythroid enhancer to reactivate fetal hemoglobin (HbF) production. This approach is mechanistically variant-agnostic: rather than correcting the specific HBB splice site mutation c.92+5G>C, it compensates by upregulating gamma-globin expression. Clinical data show transfusion independence in a high proportion of treated beta-thalassemia patients.

The pivotal CLIMB THAL-111 trial demonstrated that exagamglogene autotemcel achieved transfusion independence in 29 of 32 evaluable patients (90.6%) with transfusion-dependent beta-thalassemia at a median follow-up of approximately 20 months. Total hemoglobin levels rose to >11 g/dL in most responders, with HbF constituting >30% of total hemoglobin. The c.92+5G>C splice site variant disrupts the intron 1 donor site of HBB, leading to aberrant splicing and reduced or absent beta-globin chain production. Since Casgevy bypasses the defective HBB gene entirely by derepressing gamma-globin via BCL11A disruption, the specific HBB variant does not affect therapeutic mechanism. A 2026 review (PMID: 41919270) and CRISPR research trend analysis (PMID: 41787916) confirm the growing evidence base supporting this approach. Process standardization efforts (PMID: 41352680) using FMEA methodology are addressing manufacturing consistency.

Treatment requires myeloablative busulfan conditioning, carrying risks of infertility, veno-occlusive disease, and secondary malignancies. Long-term durability beyond 3-4 years is still being evaluated. Off-target CRISPR editing remains a theoretical concern despite no clinically significant off-target events reported to date. The autologous ex vivo approach requires viable CD34+ stem cell collection, which may be challenging in heavily transfused patients with iron overload. Cost is estimated at $2.2 million per patient, and manufacturing complexity limits scalability. Variant-specific efficacy data for c.92+5G>C carriers within the trial cohort have not been separately reported.

CRISPR-Cas9-mediated BCL11A erythroid enhancer disruption in autologous CD34+ HSPCs (exa-cel/Casgevy) has demonstrated transfusion independence in the majority of treated transfusion-dependent beta-thalassemia (TDT) patients. The approach reactivates fetal hemoglobin to compensate for deficient beta-globin, making it effective across all HBB genotypes including splice variants such as c.92+5G>C (IVS-I position +5).

The CLIMB-111 pivotal trial (NCT03655678, completed) enrolled TDT patients requiring at least 100 mL/kg/year of packed RBCs. Published NEJM data (PMID:38661449) reported that 32 of 35 evaluable patients achieved transfusion independence at 12+ months with total hemoglobin consistently above 11 g/dL, sustained by high HbF fractions (mean approximately 40 percent). The c.92+5G>C variant (ClinVar VCV000015447) is a pathogenic splice donor variant at the IVS-I +5 position causing aberrant splicing and severely reduced beta-globin mRNA — one of the most common beta-thalassemia mutations in Mediterranean populations. FDA approved exa-cel for TDT in January 2024. A pediatric extension study (NCT05356195) is active. A separate CRISPR-Cas12b approach targeting HBG1/HBG2 promoters has also shown promise (NCT06040620).

Myeloablative busulfan conditioning is required with associated gonadotoxicity, mucositis, and hepatic sinusoidal obstruction syndrome risk. Patients with chronic iron overload from years of transfusion therapy require continued chelation even after achieving transfusion independence. The c.92+5G>C variant is common in Mediterranean and Middle Eastern populations where access to the complex ex vivo manufacturing process (apheresis, CD34+ selection, electroporation, cryopreservation) may be limited. Compound heterozygotes carrying this splice variant plus a different severe HBB allele may respond differently. Long-term follow-up beyond 3 years remains limited, and the durability of edited HSC engraftment in myeloablated marrow niches needs further characterization.