Gentler Gene Therapy Eases Sickle Cell Complications
Research By: Michael Grimley, MD | Stella Davies, MBBS, PhD, MRCP | Punam Malik, MD
Post Date: May 26, 2025 | Publish Date: May 26, 2025
CBDI: Bone Marrow Transplant and Immune Deficiency | Top Scientific Achievement
A reduced-intensity gene therapy for sickle cell disease invented at Cincinnati Children’s demonstrated success in a phase 1/2 clinical trial.
Detailed findings from seven patients receiving reduced‑intensity autologous stem cell transplants using a γ‑globin lentiviral vector (GbGM) were published in May 2025 in Nature Medicine. Michael Grimley, MD, and Stella Davies, MBBS, PhD, MRCP, were co-first authors. Punam Malik, MD, who developed the therapy, was corresponding author.
The therapy works by collecting hematopoietic stem cells (HSCs) from the patient, then modifying them to carry the G16D gamma-globin gene. When infused back to the patient, the modified cells produce fetal hemoglobin (HbF-G16D), which effectively prevents red blood cells from deforming to sickle shapes.
Recipients were followed for two to seven years. All participants maintained expression of HbF-G16D and all experienced greater than 80% reductions in severe vaso‑occlusive crises. Importantly, when patients underwent transplant with reduced intensity conditioning and their genetically modified cells, they had low blood cell counts (cytopenias) for only about a week: thrombocytopenia lasted five days and neutropenia lasted eight days—all meeting predefined safety and feasibility endpoints. Notably, participants experienced shorter periods of cytopenias than typically seen after other forms of gene therapy for sickle cell disease.
“Using a reduced‑intensity single‑agent conditioning regimen opens gene therapy to more patients by lowering toxicity and resource demands—potentially including low‑resource settings,” Malik says.
The clinical trial was terminated after the seventh infusion because primary endpoints were met and industry funding had concluded. Intellectual property and responsibility for the study were fully returned to Cincinnati Children’s. The investigators recommend expanding the research to larger multi‑center trials to compare outcomes and costs against other approaches.
The gene therapy product used in the clinical trial was produced by the Translational Core Lab at Cincinnati Children’s, which has recently expanded at a new location in Sharonville, Ohio.
About the study
Cincinnati Children’s co-authors also included Archana Shrestha, PhD, Amy Shova, Charles Quinn, MD, MS, Omar Niss, MD, Carolyn Lutzko, PhD, Parinda Mehta, MD, Pooja Khandelwal, MD, Courtney Little, Sharat Chandra, MD, Sydney Felker, MD, PhD, Mengna Chi, PhD, Theodosia Kalfa, MD, PhD, Paritha Arumugam, PhD, Kristie Ramos, MD, Scott Witting, PhD, and Teresa Latham, PhD.
Experts with the University of the West Indies, Atrium Health Levine Children’s (Charlotte, NC) and the University of Pennsylvania collaborated.
This project was funded in part by Aruvant Sciences, the NHLBI’s Gene Therapy Resource Program, the Doris Duke Charitable Foundation Clinical Scientist Award, the Cincinnati Children’s Hospital Research Foundation, and the Charles H. Dater Foundation.
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| Original title: | Lentiviral gene therapy with reduced-intensity conditioning for sickle cell disease: a phase 1/2 trial |
| Published in: | Nature Medicine |
| Publish date: | May 26, 2025 |
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The Research Horizons blog features news and insights about the latest discoveries and innovations developed by the scientists of Cincinnati Children's. This blog does not provide medical advice, diagnosis, or treatment. Email researchnews@cchmc.org with questions or ideas.
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