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Explore our cutting edge research, world-class patient care, career opportunities and more.
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SAGES1 Employs the Powerful Potential of Gene Editing for Sickle Cell Disease
At St. Jude, laboratory and clinical researchers have long studied sickle cell disease, a blood disorder caused by mutations in the HBB gene, which normally encodes the β-globin subunit of adult hemoglobin.
Sickle cell disease becomes symptomatic when fetal hemoglobin expression decreases around the time of birth, giving way to the production of adult hemoglobin. This shift in expression leads to the development of the hallmark sickled red blood cells, causing episodes of severe pain, chronic organ damage, and early mortality.
Knowing that the sickling of red blood cells and subsequent symptoms diminish when fetal hemoglobin levels are high, St. Jude researchers examined how a gene editing approach, called CRISPR Cas9, increases fetal hemoglobin levels in red blood cells of patients with sickle cell disease. CRISPR-Cas9 gene editing works by using a guide RNA to direct the Cas9 enzyme to specific sequences within the genome, where Cas9 “cuts” segments of targeted DNA. By removing or replacing segments of targeted DNA, CRISPR Cas9 thereby modifies the genome and the genetic instructions for cellular behavior these DNA segments code for, such as the creation of sickled red blood cells.
Investigating the mechanisms of CRISPR-Cas9 gene editing
In 2016, Akshay Sharma, MBBS, MSc, Department of Bone Marrow Transplantation & Cellular Therapy, began working in the laboratory of Mitchell Weiss, MD, PhD, Department of Hematology chair, to investigate the genetic regulators that control fetal hemoglobin production. Weiss’s lab had previously shown that CRISPR-Cas9 disruption of a DNA-binding site for BCL11A — a known repressor of fetal hemoglobin expression — in the promoters of the fetal hemoglobin genes HBG1 and HBG2 activated their expression in adult red blood cells.
These findings raised the possibility that disrupting the same BCL11A-binding motif at these specific sites in blood stem and progenitor cells of patients with sickle cell disease could increase fetal hemoglobin to therapeutic levels. From the results of this work, and in parallel with the growing bone marrow transplantation and gene therapy programs for hematologic disorders at St. Jude, Sharma and key collaborators developed a gene editing clinical trial for sickle cell disease: the St. Jude Autologous Genome Edited Stem Cells for Sickle Cell Disease-1 (SAGES1).
Akshay Sharma, MBBS, MSc, and Bone Marrow Transplant clinical staff perform a follow-up examination on the first St. Jude patient treated on the SAGES1 clinical trial three months after she received her gene therapy.
Launching a St. Jude gene editing trial for sickle cell disease
The SAGES1 trial is significant, not only for its precise CRISPR-Cas9 gene editing approach developed in Weiss’s laboratory, but because every aspect of the trial occurs on the St. Jude campus. From clinical care to the gene editing process to cell infusion, patients benefit from the expertise across St. Jude. The SAGES1 trial enrolled its first participant in 2025, with Sharma serving as principal investigator of the trial.
Successfully translating gene therapy approaches from the bench to the bedside demands a committed team of staff and faculty with complementary expertise, working together toward a shared goal of curing devastating hematological diseases, including sickle cell disease.
Department of Bone Marrow Transplantation and Cellular Therapy
“We are the first academic institution to have infused a patient with a genetically modified hematopoietic stem cell product manufactured right here, rather than partnering with industry or a pharmaceutical company,” said Sharma. “It is a huge achievement, and it is because of our GMP [Good Manufacturing Practices] facility and the capabilities it offers in the manufacturing of gene editing products as a therapeutic for pediatric catastrophic diseases, including blood disorders and cancer.”
The story of SAGES1 is one of experimentation, discovery, and refinement that spans almost a decade from concept to enrollment. “The whole point of what we do at St. Jude is that the things we learn in the lab could someday change a patient’s life,” said Sharma. That ethos continues to fuel scientific progress and clinical advancement as SAGES1 progresses.
For now, the trial is open to young adults, ages 18 to 25, to establish basic safety and efficacy for the novel CRISPR-Cas9 gene editing approach used in SAGES1.
A team-science approach to innovation
“It is all about team science,” said Weiss. “Successfully translating gene therapy approaches from the bench to the bedside demands a committed team of staff and faculty with complementary expertise, working together toward a shared goal of curing devastating hematological diseases, including sickle cell disease.”
Data from SAGES1 will be used to further refine and innovate approaches to CRISPR-Cas9 gene editing to improve the efficacy and accessibility of the therapy, taking the concept of a cure for genetic conditions, including sickle cell disease, from promise to reality.