Can Gene Editing Be A 'Functional Cure' For Sickle Cell Disease?

A new “functional cure” for sickle cell disease may come in the form of an experimental one-time gene editing cell therapy, renizgamglogene autogedtemcel (reni-cel), according to findings published in the New England Journal of Medicine.

Reni-cel 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.

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, for his perspective on the results from the RUBY trial.

What Are We Missing In Sickle Cell Disease Treatment?

Previous gaps in the common treatment options for sickle cell disease include limited donor availability and the possibility of graft-versus-host disease.

“Gene therapy is autologous, so every patient can essentially donate to themselves. And because it is autologous, you don’t usually have graft rejection or graft-versus-host disease, so no immunosuppression is required.”

Gene Editing Sickle Cell Disease With Reni-cel

In the phase 1-2 multicenter open-label, single-group study, study investigators evaluated reni-cel, an investigational clustered regularly interspaced short palindromic repeats (CRISPR)–Cas12a gene-edited autologous hematopoietic stem-cell therapy.

“Reni-cel is a novel therapy and represents a different approach. It is still autologous, but the gene-editing technique differs from previously approved therapies in two key ways. First, it uses Cas12a instead of Cas9, which offers greater specificity,” explained Hanna.

“The more important distinction is that it mimics a natural process. Approved gene therapies typically target BCL11A binding, whereas this approach targets the HBG1 and HBG2 promoters—similar to what occurs in individuals with sickle cell disease who remain asymptomatic due to persistently elevated fetal hemoglobin. We examined the underlying mutation in those individuals and aimed to replicate it. That is the rationale behind this study: to evaluate the safety and efficacy of this approach.”

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.

The trial included 28 patients with severe sickle cell disease who were 12 to 50 years of age with ≥2 severe vasco-oclusive events per year in the previous 2 years.

What Did Reni-cel Accomplish?

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).

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.

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.

Stay up to date with the rest of our conversation with Hanna to learn more about the significance of the reduction in pain crisis for patients with sickle cell disease.

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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