Background
Phase 1–2, multicenter, open-label, single-group study (RUBY trial). 28 patients (ages 12–50) with severe sickle cell disease (≥2 vaso-occlusive events [VOEs]/year in prior 2 years). Reni-cel (renizgamglogene autogedtemcel) uses CRISPR-Cas12a gene editing to disrupt BCL11A binding sites in the HBG1/HBG2 (gamma-globin) promoters, reactivating fetal hemoglobin (HbF) to compensate for defective HbS. Myeloablative busulfan conditioning followed by single reni-cel infusion. Study was terminated early by sponsor (business reassessment, not safety); results represent unplanned analysis.
Interventions and follow up
Arm A: Single infusion of reni-cel after myeloablative busulfan conditioning (all patients; no comparator)
Primary endpoint: Safety (phase 1–2 design)
mFollow up: Median 9.5 months (range 0.7–25.2)
Primary endpoint: Safety (phase 1–2 design)
mFollow up: Median 9.5 months (range 0.7–25.2)
Results
Neutrophil engraftment: Median 23 days (range 14–29)
Platelet engraftment: Median 25 days (range 17–51)
Total hemoglobin at month 6 (n=18): 13.8 g/dL (from 9.8 g/dL baseline)
Fetal hemoglobin at month 6: 48.1% (from 2.5% baseline) — sustained thereafter
VOE-free: 27 of 28 patients had NO severe VOEs after infusion
Platelet engraftment: Median 25 days (range 17–51)
Total hemoglobin at month 6 (n=18): 13.8 g/dL (from 9.8 g/dL baseline)
Fetal hemoglobin at month 6: 48.1% (from 2.5% baseline) — sustained thereafter
VOE-free: 27 of 28 patients had NO severe VOEs after infusion
Adverse events
Main adverse events: Consistent with myeloablative busulfan-based conditioning and autologous HSCT. No unexpected reni-cel–specific safety signals. 1 patient had 2 severe VOEs post-infusion.
Conclusions
Reni-cel produced normalization of hemoglobin levels and marked elevation of HbF, with complete absence of VOEs in 27/28 patients. Despite early termination, these results support further investigation of CRISPR-Cas12a HbF induction as a curative strategy for severe SCD.
Key Limitations
Key Limitations: Single-arm, no control group. Short median follow-up (9.5 months). Study terminated early by sponsor (business decision) — long-term durability unknown. Small sample size. Myeloablative conditioning carries significant risks including infertility, infection, and secondary malignancy. Results represent unplanned analysis. Direct comparison with exagamglogene autotemcel (exa-cel, Casgevy) — approved CRISPR therapy for SCD — is not available.
Clinical Context
Exa-cel (Casgevy, CRISPR-Cas9-based) and betibeglogene sparticulenvec (Zynteglo, lentiviral) are FDA-approved gene therapies for severe SCD and beta-thalassemia. Reni-cel uses a next-generation CRISPR-Cas12a system, which may offer precision advantages. The early program termination limits its near-term clinical path despite promising early data.
References
References: Hanna R et al, NEJM 2026 (RUBY, reni-cel in SCD)