The phrase “functional cure” is used carefully in medicine — it describes an outcome in which a disease’s effects are so effectively suppressed that the patient lives as though they do not have it, even if the underlying genetic cause remains. For sickle cell disease, a condition that has caused lifelong suffering, organ damage, and premature death for 100,000 Americans and millions globally, achieving a functional cure through gene editing is one of the most profound accomplishments medicine has produced in years.
The RUBY Trial, published in the New England Journal of Medicine on April 1, 2026, has delivered exactly that result. Of 28 patients with severe sickle cell disease who were treated with renizgamglogene autogedtemcel (reni-cel) — a CRISPR-Cas12a gene editing therapy that modifies patients’ own blood-forming stem cells — 27 (96 percent) had no painful sickle cell crises for up to two years following treatment. Their average hemoglobin levels rose to near-normal levels, effectively restoring the oxygen-carrying capacity that sickle-shaped red blood cells cannot provide.
“We have seen that a benefit of this CRISPR/Cas12a gene-editing technology is that there is no rejection, so it’s different from traditional bone marrow transplants, which is standard treatment for sickle cell patients currently,” said Dr. Rabi Hanna, lead author and chair of the Pediatric Hematology-Oncology and Blood and Bone Marrow Transplant Division at Cleveland Clinic Children’s, who led the multicenter trial sponsored by Editas Medicine. “Our aim has been to achieve a functional cure to help prevent any future damage caused by sickle cell disease, and these latest results are compelling.”
How Reni-Cel Works — and Why Cas12a Matters
Reni-cel uses CRISPR-Cas12a gene editing to target the promoter regions of the HBG1 and HBG2 genes — the switches that normally suppress fetal hemoglobin production after birth. By editing these promoters, reni-cel reactivates the production of fetal hemoglobin (HbF) in adult red blood cells. Since fetal hemoglobin does not sickle, its presence in sufficient quantities effectively dilutes or displaces the dysfunctional sickle hemoglobin, preventing the cell deformation that causes sickle cell crises, organ damage, and shortened life expectancy.
This approach is distinct from Casgevy (exa-cel) — the first approved CRISPR therapy for sickle cell disease, using CRISPR-Cas9 to target BCL11A, a different suppressor of fetal hemoglobin. Reni-cel uses CRISPR-Cas12a, which has a different molecular structure and cutting mechanism from Cas9, and targets HBG1/HBG2 directly rather than through BCL11A. The two approaches achieve similar biological endpoints — fetal hemoglobin reactivation — through different molecular pathways, meaning they may offer complementary options for patients in whom one approach is less effective.
The 28 patients — four of whom were treated at Cleveland Clinic Children’s — underwent a procedure in which their stem cells were first collected and taken to a laboratory where the gene editing was performed. They then received chemotherapy to clear their bone marrow, making room for the repaired cells, which were infused back into their bodies. Within weeks of engraftment, fetal hemoglobin levels began rising. Most patients’ hemoglobin reached near-normal values within the first several months — and the patients themselves experienced what the data describe: two years without a painful crisis.
Access and What Comes Next
Reni-cel is not yet FDA-approved. The RUBY Trial data represent Phase 1/2 trial results — sufficient to demonstrate safety and early efficacy, but additional confirmatory data and FDA submission will be needed before approval. Editas Medicine, the trial sponsor, is expected to proceed with regulatory submission based on these results. The cost challenge that affects Casgevy — approximately $2.2 million per patient — will also apply to reni-cel, making equitable access a critical policy question for the approximately 100,000 Americans with sickle cell disease, most of whom are Black or Latino, a demographic that has faced persistent underinvestment in sickle cell research and treatment infrastructure for decades.
Frequently Asked Questions
Q: What were the RUBY Trial results?
A: 27 of 28 patients (96%) with severe sickle cell disease had zero painful sickle cell crises for up to two years after treatment with reni-cel. Their average hemoglobin levels rose to near-normal.
Q: How is reni-cel different from Casgevy?
A: Reni-cel uses CRISPR-Cas12a to edit the HBG1 and HBG2 fetal hemoglobin promoters directly. Casgevy uses CRISPR-Cas9 to target BCL11A. Both reactivate fetal hemoglobin but through different molecular pathways.
Q: Is reni-cel FDA-approved?
A: No. The RUBY Trial is Phase 1/2. FDA submission is expected based on these results. Casgevy is already FDA-approved and represents the current available option.
Q: How many Americans have sickle cell disease?
A: Approximately 100,000 Americans, disproportionately African American and Latino.
Q: Why is gene editing potentially better than bone marrow transplant for sickle cell?
A: Because patients use their own edited cells, eliminating the need for a matched donor and removing the risk of graft-versus-host disease — the immune attack that is the major complication of donor-based bone marrow transplants.
