One-Time Gene-Editing Therapy Gives Patients “Freedom” From Pain Crisis

An experimental one-time gene-editing cell therapy may have the potential to give patients with sickle cell disease “freedom” from frequent medical interventions and pain crises.1

According to findings, 27 out of 28 patients treated with renizgamglogene autogedtemcel (reni-cel) did not report any severe vaso-occlusive events after infusion.1

HCPLive’s nephrology team spoke with the lead author and chair of the Pediatric Hematology – Oncology & Blood and Bone Marrow Transplant Division at Cleveland Clinic Children’s, Rabi Hanna, MD, to discuss how meaningful this data is for this patient population.

“It is not only enough to survive—it is important to thrive for these patients. That’s why, in addition to this, we are excited to report and collect patient-reported outcomes,” Hanna shared. “And we can see, as we shared during ASH, that patient fatigue and physical activity are almost back to normal. So they are thriving, not only surviving.”

What Does Reni-Cel Do, and How Did Hanna Investigate It?

Reni-cel is an investigational clustered regularly interspaced short palindromic repeats (CRISPR)–Cas12a gene-edited autologous hematopoietic stem-cell therapy. The novel, autologous technique is designed to modify a patient’s own blood-forming stem cells to correct the mutation responsible for sickle cell disease, increasing fetal hemoglobin levels to prevent red blood cells from forming into sickle-shaped cells, and improving overall hemoglobin levels to reduce complications from the disease.1

The therapy differs from previously approved therapies, Hanna explains, in 2 key ways. First, it uses Cas12a instead of Cas9, offering increased specificity. Secondly, it mimics a natural process, targeting the HBG1 and HBG2 promoters. This is similar to what occurs in individuals with sickle cell disease who remain asymptomatic due to persistently elevated fetal hemoglobin.1

Hanna and colleagues examined this underlying mutation in those individuals and aimed to mimic it in a phase 1-2 multicenter, open-label, single-group study where 28 patients were treated with a single infusion of renicel after myeloblative conditioning with busulfan, a high-dose chemotherapy regimen used before allogeneic stem cell transplantation (HCT) to eliminate cancer cells and suppress the immune system.1,2

What Did Investigators See With Reni-Cel-Treated Patients?

According to the results, among 27 patients who had neutrophil and platelet engraftment by the data-cutoff date, neutrophil engraftment, the process where transplanted stem cells begin producing new, healthy blood cells in a patient's bone marrow. occurred after a median of 23 days (range, 14 to 29). Additionally, platelet engraftment, the process where newly transplanted stem cells begin producing platelets, signaling recovery in hematopoietic stem cell transplants, occurred after a median of 25 days (range, 17 to 51).1

At month 6, among 18 patients with at least 6 months of available data, the mean (±SD) total hemoglobin level (9.8±1.7 g per deciliter at baseline) had increased to 13.8±1.9 g per deciliter, and the mean percentage of fetal hemoglobin (2.5±2.5% at baseline) had increased to 48.1±3.2%. Both of these measures remained stable.1

In terms of pain crisis, 1 patient had 2 severe vaso-occlusive events after infusion. Overall, the adverse events were consistent with those that occur after myeloablative busulfan-based conditioning and autologous hematopoietic stem-cell transplantation.1

“Think of the days this is giving them back now. Even in the one patient who did have pain, that patient previously had 6 to 7 pain crises per year and had only 1 event after treatment, in the setting of infection. This is very promising data, and we will continue to follow these patients long term, including pain outcomes and, importantly, organ effects.”

Hanna further notes anecdotal data of improvement in vasculopathy or pulmonary hypertension, remarking that these metrics warrant further study. Additionally, he emphasizes that, given reni-cel is an innovative therapy, investigators will need to continue to monitor for any potential long-term side effects.

Editor’s Note: Hanna reports relevant disclosures with Chiesi USA, Inc., Swedish Orphan Biovitrum AB (Sobi), and Vertex Pharmaceuticals Incorporated.

References

1. Hanna R, Frangoul H, Pineiro L, et al. CRISPR-Cas12a Gene Editing of HBG1 and HBG2 Promoters to Treat Sickle Cell Disease. New England Journal of Medicine. 2026;394(13):1281-1291. doi:https://doi.org/10.1056/nejmoa2415550

2. Popat UR, Pasvolsky O, Bassett Jr. R, et al. Myeloablative fractionated busulfan for allogeneic stem cell transplant in older patients or patients with comorbidities. Blood Advances. 2023;7(20):6196-6205. doi:https://doi.org/10.1182/bloodadvances.2023010850

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