Two groundbreaking CRISPR-based gene therapies are showing promising early results in clinical trials for sickle cell disease, offering new hope for patients with this devastating genetic blood disorder that affects approximately 100,000 people in the United States.
RUBY Trial Demonstrates Safety and Efficacy
Researchers from the multicenter RUBY Trial presented encouraging preliminary data on EDIT-301, an experimental one-time gene editing cell therapy that modifies patients' own blood-forming stem cells to correct the mutation responsible for sickle cell disease. The results were presented at the European Hematology Association Hybrid Congress in Frankfurt, Germany.
The first four patients in the trial, including two treated at Cleveland Clinic Children's, underwent a comprehensive treatment process where their stem cells were collected for gene editing. Following chemotherapy treatment to clear existing bone marrow, the repaired cells were infused back into their bodies.
"New treatments like this are critical for people who have sickle cell disease," said Dr. Rabi Hanna, director of the pediatric blood and bone marrow transplant program at Cleveland Clinic Children's and principal investigator. "These initial results provide hope that this new technology will continue to show progress as we work toward creating a possible functional cure for this devastating and life-threatening disease."
The trial marks the first clinical use of CRISPR/Cas12 technology to edit human cells, representing a highly precise tool for modifying blood stem cell genomes to enable robust, healthy blood cell production. Data showed new white blood cells in all four patients at approximately four weeks with no severe adverse effects. Critically, patients achieved normal hemoglobin levels and remained free of sickle cell disease's characteristic pain attacks for periods of seven to 11 months following therapy.
Alternative CRISPR Approach Shows Promise
A separate research team led by James LaBelle at the University of Chicago has published encouraging results from a Phase I/II clinical trial using OTQ923, another stem cell gene therapy approach for sickle cell disease. This therapy utilizes CRISPR-Cas9 gene-edited hematopoietic stem and progenitor cells with disrupted HBG1 and HBG2 gene promoters.
The approach builds on scientific understanding that elevated levels of fetal hemoglobin in red blood cells protect against sickle cell disease's adverse effects by replacing deformed adult hemoglobin. In preclinical experiments on immunodeficient mouse models, OTQ923 progeny increased fetal hemoglobin levels.
Participants with severe sickle cell disease who received their own CRISPR-Cas9 edited stem cells showed increased fetal hemoglobin levels within red blood cells and reported decreased vaso-occlusive events. This study represents the first to target this specific genetic locus and utilize cryopreserved stem cells for sickle cell disease treatment.
Addressing Critical Medical Need
Sickle cell disease is an inherited blood disorder affecting predominantly African American populations, with approximately one in 365 African American babies born with the condition. The disease leads to production of abnormal hemoglobin, causing red blood cells to form a sickle shape that blocks narrow blood vessels, resulting in severe pain, organ damage, and reduced life expectancy.
Current treatment options remain limited, with most patients relying on medications that modify disease severity and treat symptoms. Despite available therapies, the average life expectancy for sickle cell patients is in the mid-40s. While blood or marrow transplants can cure the disease, they often require sibling donors and carry risks of severe graft-versus-host disease.
"The biggest take-home message is that there are now more potentially curative therapies for SCD than ever before that lie outside of using someone else's stem cells, which can bring a host of other complications," commented LaBelle. "The data from this trial supports bringing on similar gene therapies for SCD and for other bone marrow-derived diseases."
These parallel developments in CRISPR-based gene therapies represent significant advances in expanding the therapeutic toolbox for sickle cell disease, potentially offering curative alternatives to traditional bone marrow transplants while avoiding complications associated with donor-derived treatments.
