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CHOP Researchers Pioneer Gene Therapy to Treat XLSA in a Preclinical Model

X-linked sideroblastic anemia (XLSA) is a rare congenital anemia — fewer than 200 cases have been diagnosed — caused by mutations in the Alas2 gene.
The Findings
Researchers at Children's Hospital of Philadelphia have pioneered a preclinical model of X-linked sideroblastic anemia (XLSA) and successfully treated the rare disease with an in vivo gene therapy. Using a targeted lipid nanoparticle platform technology, the team designed small animal models that exhibited hallmark symptoms of XLSA, including a buildup of abnormal red blood cells called sideroblasts.
The researchers then engineered a lentiviral viral vector, called X-ALAS2-LV, to deliver the corrected Alas2 gene that is dysfunctional in patients with XLSA. The gene therapy reversed symptoms of XLSA in the models, boosted hemoglobin, and improved survival rates. The preliminary findings suggest that the vector could be curative in XLSA patients, according to the study authors, but more clinical studies are needed.
Why It Matters
XLSA is an extremely rare congenital anemia — fewer than 200 cases have been diagnosed — caused by mutations in Alas2. It primarily affects adult men, though new cases of girls and women with the disease are beginning to emerge. Alas2 provides instructions for making an enzyme called erythroid ALA-synthase, which is necessary to produce hemoglobin in the bone marrow. The mutation disrupts this process, leading to excess iron in the body. Over time, the iron buildup can cause heart disease and liver damage.
Current treatment options for patients with XLSA are limited to pyridoxine supplements, blood transfusions, and allogeneic hematopoietic stem cell transplantation, which is only accessible to a small subset of patients. The absence of a suitable research model for XLSA has hindered the development of a gene therapy to potentially cure the disease.
Who Conducted the Study
Stefano Rivella, PhD, the Kwame Ohene-Frempong Endowed Chair in Pediatric Hematology at CHOP, led the research team, alongside researchers at the University of Pennsylvania's Perelman School of Medicine. Carlo Castruccio Castracani, PharmD, PhD, a Clinical Research Study Manager in the Rivella Lab, was the study's lead author. Laura Breda, PhD, a Research Assistant Professor in the Division of Hematology, and Amaliris Guerra, PhD, a Research Scientist in the Division of Hematology, co-authored the study.
How They Did It
Since a complete knock-out of the Alas2 gene was expected to be lethal, the scientists pursued an inducible conditional knockout model as a feasible alternative to study the disease. This genetic technique enables researchers to temporarily deactivate a gene in a specific tissue or at a particular time. Once the research models were created, the scientists tested levels of anemia to see how closely the models mimicked the effects of XLSA in humans. The researchers then tested the X-ALAS2-LV vector's ability to reverse disease in the models. Compared to control models, the researchers found that no iron accumulation was detected in the mitochondria of the animal models treated with the gene therapy, and they demonstrated improved glycolysis.
Quick Thoughts
"These are very dramatic results," Dr. Rivella said. "The new model and vector may hold the keys to transforming the lives of XLSA patients."
What's Next
In future studies, the team aims to adapt the model to investigate pharmacological treatment and the possibility of in vivo gene editing.
Where the Study was Published
The study appeared in the journal Blood and was presented at the American Society of Gene & Cell Therapy's 27th annual meeting. Read more in a related CHOP press release.