First of Its Kind Gene Therapy Model Offers Hope for X-Linked Sideroblastic Anemia Treatment

Researchers at Children’s Hospital of Philadelphia (CHOP) and the University of Pennsylvania Perelman School of Medicine pioneered a first of its kind gene therapy model that offers a potential breakthrough in treating X-linked sideroblastic anemia (XLSA), a rare congenital anemia caused by mutations in the ALAS2 gene crucial for the synthesis of heme, a key compound in hemoglobin. This study marks the first time researchers studied gene therapy to treat this disease, which the authors underscore could have an impact on a broad spectrum of diseases. The research was published today on the cover of the journal Blood.

XLSA has traditionally impacted men under the age of 40, however, researchers noted that new cases of girls and mid-life women with the rare disease are beginning to emerge. Patients with XLSA experience a disruption in heme synthesis, leading to a spectrum of issues such as severe anemia and iron overload, which can cause symptoms like extreme fatigue, shortness of breath and growth delays. Most XLSA patients are dependent on pyridoxine supplements, which provide vitamin B6, and blood transfusions to treat the disease. The sole potential cure for XLSA is currently an allogenic stem cell transplant, which is only an option for a limited number of patients due to the need for a compatible donor, high cost and intense chemotherapy involved, which can have significant side effects. 

In this study, researchers used a newly created preclinical model to evaluate for the first time whether gene therapy could offer a potentially transformative treatment for these patients. Carlo Castruccio Castracani, PharmD, PhD, the study’s lead author and the team’s Clinical Research Study Manager, used a targeted lipid nanoparticle (LNP) platform technology, established by Hamideh Parhiz, PharmD, PhD, a co-senior study author and Assistant Professor of Pharmacology at Penn Medicine, to induce the deletion of the Alas2 gene in hematopoietic stem cells. 

Upon deletion of the ALAS2 gene, the researchers subsequently observed classic symptoms of XLSA like anemia and enlargement of the spleen. The model also allowed the researchers to note features of this disease that are significant in humans, such as ring sideroblasts, a type of immature red blood cell. 

“The lack of ALAS2 in the preclinical model was associated with an expansion in the number of premature red cells, with a high proportion undergoing cell death,” said Castruccio Castracani. “We also observed defects in metabolism and mitochondria structure and performance, which prevented healthy red cells from forming and led to severe anemia.”

Castruccio Castracani and his team developed a lentiviral vector that activated the human ALAS2 gene in erythroid cells, or cells that serve as precursors to normal red blood cells. They found that this gene therapy approach significantly boosted hemoglobin and red blood cell levels, helping normalize hormone levels that control red blood cell production. Preclinical trial subjects that received optimal doses of the vector showed significant improvements in hemoglobin levels, spleen health, and iron balance. 

“This new model and vector may hold the keys to transforming the lives of XLSA patients,” said Stefano Rivella, PhD, a senior author, the Kwame Ohene-Frempong Endowed Chair in Pediatric Hematology research and a faculty member in the Division of Hematology at CHOP. “In future studies, we aim to adapt this model to investigate pharmacological treatment and in vivo gene editing for a broader range of diseases.” 

Castruccio Castracani et al. “An erythroid-specific lentiviral vector improves anemia and iron metabolism in a new model of XLSA.” Blood. January 2, 2025. DOI: 10.1182/blood.2024025846.