After Sickle Cell Gene Therapy, What Comes Next?

Gene therapy, which uses a patient's own genetically modified cells as a curative treatment, avoiding the need for a matched donor, has produced strong early results for patients with sickle cell disease, freeing many from the vaso-occlusive crises that previously defined their disease course. Even so, 2 areas of outcome remain under active study: organ function over time, and psychosocial adjustment following treatment.

Stacey Rifkin-Zenenberg, DO, MS, FAAP, FAAHPM, Section Chief of Pediatric Pain and Palliative Care and a pediatric hematologist/oncologist in Hackensack, NJ, discussed both the current landscape and the long-term questions researchers are still working to answer.

Sickle Cell Gene Therapy: Early Outcomes

"What we're now seeing is that most of the patients that have received gene therapy are actually transformed," Rifkin-Zenenberg said. "Their sickle cell is transformed. They don't have crises."

At the same time, she pointed to 2 areas she is watching closely as more patients move further out from treatment:

"I'd like to see how they do as they go through time with their clinical organ function, and how they are also doing from a psychosocial point of view."

Organ Function After Gene Therapy

Rifkin-Zenenberg did not specify which organ systems concern her most, but her point tracks with what the broader literature has found so far.

Sickle cell disease can cause progressive organ damage well before a curative treatment ever happens, so a patient's post-treatment organ trajectory reflects both that pre-existing burden and whatever longer-term effects gene therapy itself may carry.

Trials to date have shown durable disease modification, but the toxicity data available so far is largely short-term, meaning long-term organ outcomes are still being collected rather than fully known.

Psychosocial Outcomes After Curative Treatment

A cure doesn't necessarily mean an easy transition. In a mixed-methods study of adult sickle cell disease patients after allogeneic stem cell transplantation, most reported improvements in social health, but emotional struggles and feelings of being overwhelmed were also common, and many wanted more psychological counseling.¹

Whether gene therapy recipients face a similar adjustment is unclear — this evidence comes from transplant patients, and comparable research on gene therapy patients doesn't yet exist.

Sickle Cell Disease: Clinical Implications for Curative Treatment

Rifkin-Zenenberg noted that discussion of curative options should begin early, regardless of the current state of long-term outcome data.

For patients and families, that leaves 2 distinct pieces of information: sustained elimination of crises has been observed in most treated patients so far, and organ function and psychosocial outcomes remain under active follow-up rather than fully characterized.

Editor’s Note: Rifkin reports relevant disclosures with Bluebird Bio and Vertex Pharmaceuticals Incorporated.

References

1. Sharma A. How I treat sickle cell disease with gene therapy. Blood. 2024;144(26):2693-2705. doi:10.1182/blood.2024024519

2. Tardif M, Saby M, Forté S, Pincez T. The journey of gene therapy in sickle cell disease: how molecular advances meet clinical care. Cells. 2026;15(10):939. doi:10.3390/cells15100939

3. Krishnamurti L, Arnold SD, Haight A, et al. Sickle Cell Transplantation Evaluation of Long-term and Late Effects Registry (STELLAR) to compare long-term outcomes after hematopoietic cell transplantation to those in siblings without sickle cell disease and in nontransplanted individuals with sickle cell disease: design and feasibility study. JMIR Res Protoc. 2022;11(7):e36780. doi:10.2196/36780

4. Lanzkron S, Coleman-Cowger VH, Thompson AA, Carroll CP, Clemons T, DeBaun M, Kanter J, Malik P, Manwani D, Pierciey FJ, Walters MC, Alai S. Cure Sickle Cell Initiative recommendations on common data elements for sickle cell disease gene therapy trials. Blood Adv. 2026;10(11):3960-3965. doi:10.1182/bloodadvances.2025019400