Researchers at Children's Hospital of Philadelphia (CHOP) pioneered a new model that offers a potential breakthrough in treating beta-thalassemia, a severe blood disorder, using a novel radiation-free conditioning regimen. The authors presented the findings from their study at the American Society of Gene & Cell Therapy's (ASGCT) 27th Annual meeting in Baltimore, Maryland last week.
The innovative model uses particles decorated on their surface with specific molecules (antibodies) to bind and deliver genetic material directly to the blood stem cells. This process avoids the severe side effects of chemotherapy or radiation in conventional conditioning for allogenic and autologous HSC transplantation (HSCT), such as lung and brain potential toxicity, sterility, secondary malignancies, and delayed recovery.
In this study, researchers used a mouse model of beta-thalassemia to deplete defective bone marrow cells with the specialized particles that deliver mRNA to drain resident thalassemic cells from the bone marrow, allowing for successful grafting of healthy donor cells. The use of modified mRNA allowed scientists to prevent expression of the mRNA in the liver, avoiding depletion of hepatocytes and overall liver toxicity.
The regimen significantly improved the health of the models with beta-thalassemia. After treatment, about 30% of the red blood cells (RBCs) were healthy donor cells, and their hemoglobin levels rose from 7.4g/dL to 10g/dL on average. Additionally, other critical blood parameters showed marked improvement, indicting effective overall improvement of beta-thalassemia pathophysiology.
In the future, researchers hope this non-genotoxic conditioning regimen can evolve research in the field, helping to revolutionize HSCT procedures and improve outcomes for patients with blood disorders.
"This model could be a game changer for patients with nonmalignant blood genetic disorders, especially those who require high levels of donor blood stem cells for effective treatment, and patients whose condition is incompatible with traditional chemotherapy," said Laura Breda, PhD, the study's author and a research assistant professor with the Division of Hematology at CHOP. "We would like to see our findings applied to a broader range of genetic diseases requiring hematopoietic stem cell transplantation. We believe this alternative conditioning regimen could significantly reduce toxicity, potentially preserving fertility and improving quality of life for patients."
Breda et al, "Improvement of Disease Phenotype in Beta-Thalassemic Mice with a Novel Radiation-Free Conditioning Regimen of Pro-Apoptotic mRNA." American Society of Gene and Cell Therapy Annual Meeting; May 7-11, 2024; Baltimore, Maryland.
