Rabi Hanna, MD

First-Generation Gene Editing in Sickle Cell Faces Real-World Limits Despite Breakthrough Results

Reni-cel Builds on Promising Early Clinical Gains

Emerging data on renizgamglogene autogedtemcel (reni-cel) continue to position gene editing as a potential “functional cure” for 

, with early-phase findings demonstrating sustained increases in fetal hemoglobin and marked reductions in vaso-occlusive events.

As previously reported, the investigational therapy uses a CRISPR gene editing–Cas12a approach to modify autologous hematopoietic stem cells, enabling increased fetal hemoglobin production and prevention of red blood cell sickling.

However, experts caution that current approaches represent an early iteration of gene-based therapies.

 of our conversation with Rabi Hanna, MD, the lead author and chair of the Pediatric Hematology – Oncology & Blood and Bone Marrow Transplant Division at Cleveland Clinic Children’s, for insights into pain crisis reductions and its mechanism as a “functional cure”.

“First-Generation” Therapy Still Faces Safety and Delivery Challenges

, Rabi Hanna emphasized that, despite strong clinical outcomes, significant limitations remain in how these therapies are delivered.

“This is really very exciting in terms of seeing a result of gene therapy, but I would call this first-generation gene therapy. We need advances in conditioning—right now we are using myeloablative busulfan, which is very strong and can cause long-term side effects, including infertility. It is on us to find better ways to deliver this without those unnecessary risks,” Hanna said.

A key barrier is the continued reliance on myeloablative conditioning, as well as inefficiencies in stem cell collection and manufacturing. Patients with sickle cell disease often require multiple collection cycles due to disease-related bone marrow challenges, and current gene-editing processes require large numbers of stem cells, increasing time and resource burden.

Access, Cost, and Development Hurdles Limit Broader Adoption

Despite its promise, gene therapy remains limited by cost and infrastructure requirements, restricting availability to specialized centers.

Broader structural challenges are also emerging. A program sponsored by Editas Medicine was discontinued despite encouraging results, reflecting the financial and logistical barriers associated with late-stage development.

These challenges underscore the need for more flexible regulatory pathways and new payment models, particularly for rare and resource-intensive therapies, to ensure broader and more equitable access.

“Functional Cure” Translates to Real-World Patient Freedom

Although gene editing does not eliminate all aspects of disease biology, its ability to restore red blood cell function has led clinicians to describe it as a functional cure.

“I use the word functional cure quite a lot, because I want to make sure patients understand we are curing the red blood cells, not the rest of the body—but what we are seeing is that this is really giving them freedom to pursue their dreams. I have patients now going to nursing school, others doing things like skydiving that they could never have imagined before,” Hanna said.

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

Hanna R, Frangoul H, Pineiro L, et al. CRISPR-Cas12a Gene Editing of 

 Promoters to Treat Sickle Cell Disease. 

Hanna R. One-Time Gene-Editing Therapy Gives Patients “Freedom” From Pain Crisis. HCPLive. Published April 17, 2026. Accessed April 21, 2026. 

https://www.hcplive.com/view/one-time-gene-editing-therapy-gives-patients-freedom-from-pain-crisis

Hanna R. Can Gene Editing Be A “Functional Cure” For Sickle Cell Disease?. HCPLive. Published April 16, 2026. Accessed April 21, 2026. 

https://www.hcplive.com/view/can-gene-editing-be-a-functional-cure-for-sickle-cell-disease

Videos

Hanna explains the real-world barriers to implementing gene editing therapies in sickle cell disease. 

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 

 “freedom” from frequent medical interventions and pain crises.

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

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.

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.

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.

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).

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.

“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.

Popat UR, Pasvolsky O, Bassett Jr. R, et al. Myeloablative fractionated busulfan for allogeneic stem cell transplant in older patients or patients with comorbidities. 

https://doi.org/10.1182/bloodadvances.2023010850

Hanna describes the "freedom" patients with sickle cell disease reported after being treated with reni-cel, a one-time edited gene therapy. 

Can Gene Editing Be A '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 

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.

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.”

data on burnout rates in physicians who treat sickle cell disease at 60%

, partially attributed to structural barriers in patient care.

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.

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. 

Hanna, MD, shares results from reni-cel, a one-time gene editing therapy for patients with sickle cell disease. 

Rabi Hanna, MD

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