Evaluating Gene Editing Therapy Reni-Cel for Severe Sickle Cell Disease

There are currently 2 FDA-approved gene therapy treatments available for sickle cell disease (SCD)—Vertex Pharmaceuticals' and CRISPR Therapeutics’ gene editing therapy exagamglogene autotemcel (exa-cel; marketed as Casgevy) and bluebird bio’s gene addition therapy lovotibeglogene autotemcel (lovo-cel; marketed as Lyfgenia)—but development of new genomic medicine options for SCD remains ongoing with the aim of filling in gaps in need unserved by the current options. One such investigational candidate is renizgamglogene autogedtemcel (reni-cel, previously known as EDIT-301), a CRISPR-Cas12a gene editing candidate for severe SCD that was evaluated in the phase 1/2 RUBY clinical trial (NCT04853576).

At the 67th American Society of Hematology (ASH) Annual Meeting and Exposition, held December 6 to 9, 2025, in Orlando, Florida, CGTLive® spoke to Rabi Hanna, MD, the chairman of the Division of Pediatric Hematology & Oncology and BMT at Cleveland Clinic Children's, shortly before he presented new data from RUBY at the conference. Hanna went over the key findings he would be presenting and also spoke about areas of interest for further research in SCD gene therapy.

CGTLive: Can you tell us about what you're presenting at ASH this year?

Rabi Hanna, MD: I'm going to give an update on the RUBY trial. It is basically a gene editing therapy for patients with a severe phenotype of SCD. The unique things about this study is it is incorporating a novel (that it is not something commercially available): reni-cel. It is basically using CRISPR-Cas12a to target the hemoglobin G1/G2 gene. What we are trying to do is actually mimic what's naturally occurring as persistent fetal hemoglobin in patient with SCD. As background, not all patients with SCD have a very severe phenotype. For some of them who have this kind of a mutation that leads to elevation in the fetal hemoglobin, it tends to be protective. So in this gene editing approach, we are trying to mimic what happens in nature.

In my presentation, I will give an update on the 40 patients that were enrolled on this study, with a median age of 26. It is important to highlight that 7 of these patient were adolescent (younger than 18 years old). The data consistently showed to really benefit these patients, and that the safety profile is what we expect when we use a busulfan myeloablative regimen.

I am very happy to report that there was no death in this group of patients. Now, with the follow-up of close to 13.5 months, and 4 of the patients having more than 2 years of follow-up, we see that 38 out of 40 patients are pain-free. This is really fantastic in terms of efficacy. [Data were] similar in terms of engraftment to what we have reported previously: neutrophil engraftment around 24 days and platelet engraftment around 21 days posttransplant, and most of the side effect of mucositis and fever neutropenia are what we expect with the use of myeloablation.

The additional information we are reporting today at ASH 2025 is patient-reported outcomes. It's so important to see, in addition to the biological response, are we seeing any improvement [in patient-reported outcomes]? I'm happy to report that both the pain reported in terms of scale is close to normal, and also the physical activity scale is almost back to normal for all of those surveyed (the patients that have been [followed] more than 12 months).

How would you summarize the big-picture implications of this new data?

I think this is really exciting to make sure that we have more options for our patients who are having severe complications from SCD. Now we have at least 2 FDA-approved gene therapies—one is lovo-cel, and the second is exa-cel—and reni-cel is exciting. I'm happy to see also that there was a presentation at ASH yesterday on the expansion of the age from below the age of 12 years to hopefully down to 5 years for the use of exa-cel.

Are there any areas of interest for further study in this space that you could discuss?

I think this is really what I consider "gene therapy 1.0." I am so excited and looking forward to the next generation of clinical trials that could use nonmyeloabative chemotherapy because it's still very hard for our patients to go and get this busulfan [regimen]. So it's exciting that there are some preclinical data about using nonmyeloablative regimens that I hope in the next year or 2 will be ready to start clinical trials.

The second really important thing to hopefully see development is in vivo gene therapy. Ex vivo gene therapy, which is what has been used, is really showing great promise, but it has limited access. This modality cannot be done in low-income countries where most of the population affected with SCD live. So we need to develop more in vivo gene therapy strategies where it could be implemented in low-income countries.

This transcript has been edited for clarity.

For more coverage of ASH 2025, click here.

REFERENCE
1. Hanna R, Frangoul H, Pineiro L, et al. CRISPR-Cas12a gene editing of the HBG1/2 promoters leads to sustained normalization of total hemoglobin and increased fetal hemoglobin in patients with severe sickle cell disease: Updated Results from the RUBY trial. Presented at: ASH 2025 Annual Meeting. December 6-9, 2025; Orlando, FL. Abstract #4314