CRISPR Therapy Moves Into Younger Children

“None of the children with transfusion-dependent β-thalassemia had transfusions after the 60-day washout period, and none of the children with sickle cell disease had vaso-occlusive crises after exa-cel infusion”Frangoul et al.

Despite advances in supportive care, many patients continue to experience progressive organ damage throughout childhood and adolescence. Strokes, pulmonary complications, kidney injury and chronic pain remain common in sickle cell disease, while repeated transfusions expose patients with β-thalassaemia to iron overload that can damage the heart, liver and endocrine system.

For decades, the only established curative treatment has been allogeneic stem-cell transplantation. Although highly effective, the procedure depends on finding a suitable donor and carries risks including graft-versus-host disease, graft failure and long-term immunological complications. As a result, many children who might benefit from curative treatment never receive it.

Researchers reactivate a dormant haemoglobin programme

»Despite optimized supportive therapy, children living with sickle cell disease and transfusion-dependent beta thalassemia carry a significant disease burden from a very young age, with progressive complications leading to the irreversible and life-shortening consequences of these diseases,« said Franco Locatelli, Director of the Department of Paediatric Haematology and Oncology at Bambino Gesù Children’s Hospital in Rome and one of the study’s senior investigators.

CASGEVY is built on a biological insight that emerged long before CRISPR entered the clinic. Humans naturally produce fetal haemoglobin before birth, but expression falls rapidly during infancy as adult haemoglobin takes over. Individuals who continue to produce unusually high levels of fetal haemoglobin often experience milder forms of sickle cell disease and β-thalassaemia. Rather than correcting the underlying HBB mutation directly, exa-cel seeks to recreate this protective state.

The therapy uses CRISPR-Cas9 to edit a regulatory region controlling the gene BCL11A in autologous haematopoietic stem and progenitor cells. BCL11A normally suppresses fetal haemoglobin production after birth. Disrupting an erythroid-specific enhancer of the gene allows fetal haemoglobin expression to resume, providing red blood cells with an alternative form of haemoglobin that can compensate for the defective adult protein. The edited stem cells are then returned to the patient following myeloablative conditioning with busulfan, where they engraft and repopulate the bone marrow.

The strategy has already proved effective in adolescents and adults. Earlier studies demonstrated that exa-cel could eliminate severe vaso-occlusive crises in most patients with sickle cell disease and free the majority of patients with β-thalassaemia from chronic transfusion requirements. The latest studies asked whether the same approach could work even earlier in life, before years of disease-related damage had accumulated.

The new data come from the CLIMB THAL-141 and CLIMB SCD-151 studies, ongoing international phase 3 trials evaluating exa-cel in children aged 5 to 11 years. Fifteen children with transfusion-dependent β-thalassaemia and eleven with severe sickle cell disease received treatment. The rationale for moving gene editing into younger patients was straightforward: if the therapy could be administered safely before substantial organ damage had occurred, its long-term clinical benefit might be even greater than that observed in adolescents and adults.

The answer was unexpectedly consistent across both diseases.

Children become transfusion-free and crisis-free

Among children with β-thalassaemia, eight had accumulated sufficient follow-up to be evaluated for the primary endpoint. All eight became transfusion independent for at least twelve consecutive months. None required further transfusions after the post-treatment washout period, and transfusion independence persisted throughout follow-up. The mean duration of transfusion independence reached 23.4 months, with some children remaining transfusion-free for more than two years.

“These data represent a profoundly important step forward, and I look forward to the possibility of providing earlier intervention to prevent complications in children”Franco Locatelli in a press release, Bambino Gesù Children’s Hospital

Laboratory measurements mirrored these clinical improvements. Haemoglobin concentrations rose into the normal range for age, while fetal haemoglobin levels increased rapidly after treatment and remained stable. More than 99% of circulating red blood cells expressed fetal haemoglobin, indicating that the edited stem cells had successfully repopulated the blood system.

The results in sickle cell disease were equally striking. Before treatment, participants experienced frequent severe vaso-occlusive crises, often requiring hospitalisation. After exa-cel infusion, no vaso-occlusive crises occurred in any treated child during the reported follow-up period.

All eight evaluable participants achieved the primary endpoint of remaining free from severe vaso-occlusive crises for at least twelve consecutive months. None required hospitalisation for such events. The mean duration of crisis-free follow-up reached 19 months.

Again, the biological data supported the clinical observations. Fetal haemoglobin levels rose to approximately 50% and remained above levels thought to protect against red-cell sickling. More than 98% of circulating red blood cells expressed fetal haemoglobin, creating a near-uniform population of protected cells.

Investigators also detected stable editing levels in peripheral blood and bone marrow stem cells throughout follow-up, suggesting durable engraftment of the modified stem-cell population.

Conditioning now limits the therapy more than editing

The study also highlights how the main challenges facing gene editing have evolved.

The CRISPR modification itself appeared highly effective and durable, and investigators observed no evidence of graft failure, treatment-related malignancy or unexpected toxicities attributable to genome editing. Instead, the most serious complications arose from the conditioning regimen required before transplantation.

Every participant experienced at least one grade 3 or grade 4 adverse event. Most reflected the expected consequences of busulfan-based myeloablation and stem-cell transplantation, including febrile neutropenia, thrombocytopenia and stomatitis.

Two children with β-thalassaemia developed severe veno-occlusive liver disease associated with busulfan conditioning. One recovered without long-term consequences. The second developed multiorgan failure and pneumonia and subsequently died. Investigators and the independent monitoring committee concluded that the event was attributable to busulfan exposure rather than the CRISPR editing procedure itself. No graft failures, treatment-related cancers or safety signals suggesting off-target genome editing were reported during the study period.

The findings therefore reinforce a trend that is becoming increasingly apparent across genetic medicine: the principal limitation of many current gene-editing therapies may no longer be whether they work, but how safely they can be delivered. In both disorders, the therapeutic effect of exa-cel was robust, durable and biologically coherent. The remaining challenge lies largely in reducing the toxicity associated with conditioning regimens that are still required to replace the patient’s haematopoietic system.

Nevertheless, the clinical implications are substantial. Children with sickle cell disease often accumulate neurological, pulmonary and renal injury long before adulthood, while repeated transfusions in β-thalassaemia can lead to iron overload affecting the heart, liver and endocrine system. A therapy capable of restoring near-normal haemoglobin biology during childhood could potentially alter the lifelong trajectory of both diseases.

»These data represent a profoundly important step forward, and I look forward to the possibility of providing earlier intervention to prevent complications in children and for families who have had limited potentially curative options to date,« said Locatelli.

Longer follow-up will be needed to determine whether the benefits persist for decades and whether earlier treatment ultimately changes long-term outcomes. Nevertheless, the consistency of the responses across both diseases suggests that CRISPR-based therapies are beginning to move beyond rescue treatment for advanced disease and towards intervention at a stage when lifelong complications may still be preventable.

The study was led by Haydar Frangoul and Franco Locatelli at the Children’s Hospital at TriStar Centennial, Nashville, and IRCCS Ospedale Pediatrico Bambino Gesù, Rome, respectively. It was funded by Vertex Pharmaceuticals and CRISPR Therapeutics, and it was published in New England Journal of Medicine on 11 June 2026. The data was also presented in a press release by Vertex Pharmaceuticals on 11 june 2026.