CHOP Researchers Discover Lentiviral Gene Transfer Enhances Alpha Globin Production for Alpha Thalassemia Treatment

Researchers at Children's Hospital of Philadelphia (CHOP) and the University of Pennsylvania Perelman School of Medicine have made significant strides in the fight against Alpha Thalassemia (AT), a severe blood disorder. Their innovative model, detailed in the journal Blood, promises a new avenue for developing therapies to treat this condition.

Alpha Thalassemia affects thousands of children annually, particularly in regions such as South-East Asia, India, the Middle East, and the Mediterranean. While the genetic trait can offer some protection against malaria and result in mild anemia when inherited from one parent, the situation becomes dire when both parents are carriers of defective genes. Children born with severe AT often face life-threatening conditions without in utero intervention and require continuous blood transfusions and extensive medical care throughout their lives.

Recent advancements in treating blood disorders like beta thalassemia and sickle cell disease have seen remarkable success. However, Alpha Thalassemia has not attracted similar attention, despite its growing prevalence. Dr. Stefano Rivella, PhD, a senior author of the study and a faculty member in the Division of Hematology at CHOP, emphasized the need for new research tools and methods to address this gap. "Our hope is that generating animal models will provide a powerful tool for future research, along with avenues of investigation for human patients," he stated.

Currently, the only therapeutic option for severe AT patients is allogeneic bone marrow transplantation (BMT), which requires a suitable donor. The development of adult mouse models for AT has been a significant challenge, limiting research into new treatments.

In their groundbreaking study, the researchers created an innovative model by deleting the alpha globin genes in adult mice. They utilized a lipid nanoparticle (LNP) containing mRNA to induce the deletion, resulting in the production of abnormal red blood cells (RBC) with faulty hemoglobin, known as HbH. This abnormal hemoglobin tightly binds oxygen, preventing its proper delivery to tissues and causing severe hypoxia. This targeted LNP platform technology was established by Dr. Hamideh Parhiz, a co-senior author of the study and Assistant Professor of Medicine at Penn Medicine.

After the deletion of the alpha globin genes, the mice exhibited decreased oxygen levels similar to those observed in severe AT patients. The abundance of RBCs that could not transport oxygen posed a critical health threat. The researchers confirmed that this model could be used to test new therapies, including genetic treatments, for improving clinical care in human patients.

Dr. Rivella and his team, including Dr. Laura Breda, Dr. Maxwell Chapell, Dr. Lucas Tricoli, and Dr. Amaliris Guerra, developed a method for gene complementation to repair defective genetic traits through hematopoietic stem cell modification and transplantation. They utilized a lentiviral vector, ALS20aI, to express human alpha globin in the mice. This vector produced high levels of human alpha globin, which sustained the mice and enhanced normal hemoglobin production. Continual bone marrow transplantation ensured ongoing expression of human alpha globin, demonstrating ALS20aI's effectiveness in providing long-lasting corrections to AT.

"This innovative approach represents a much-needed step forward in the treatment of Alpha Thalassemia," said Dr. Rivella. He expressed optimism about future research and the potential for improved patient outcomes with fewer complications over time.

The research received funding from various sources, including CHOP's Research Institute, the National Heart, Lung, and Blood Institute, and several NIH grants. The Pathology Core Laboratory at CHOP's Research Institute provided essential services such as histological, immunohistochemical, and imaging support.

The successful development of this model marks a significant milestone in the quest to find effective treatments for Alpha Thalassemia, offering hope for better management and care for patients afflicted by this severe blood disorder.