New Gene Therapy Clinical Trial Launches for Patients with Transfusion-Dependent Beta-Thalassemia

Beta-thalassemia is an inherited genetic blood disorder caused by reduced or absent production of the beta chains of hemoglobin, the protein responsible for transporting oxygen throughout the body.

Patients with transfusion-dependent beta-thalassemia require lifelong regular blood transfusions and continuous iron-chelation therapy to prevent iron overload. Although transfusions are life-saving, long-term treatment may lead to damage to multiple organs—primarily due to excess iron—and can significantly affect quality of life.

Currently, hematopoietic stem cell transplantation from a compatible donor represents a potentially curative treatment. However, it is available only to a minority of patients and carries significant risks.

More recently, gene-editing-based therapy using genetically modified hematopoietic stem cells has become available in Italy for selected patient groups.

The launch of this new clinical trial comes at a time when existing advanced therapies for beta-thalassemia, although already approved, still have important limitations related to patient age; specific genetic characteristics; treatment availability.

The new protocol is an evolution of the pilot clinical trial launched in 2015 by Fondazione Telethon and IRCCS Ospedale San Raffaele, which involved correcting patients' hematopoietic stem cells using a lentiviral vector.

In that study (NCT02453477), several patients experienced a significant reduction in transfusion requirements and, in some cases, achieved long-lasting transfusion independence (see Marktel et al., Nature Medicine, 2019).

Based on those results, researchers at SR-Tiget optimized the stem cell manufacturing process by shortening the cell culture period and improving the efficiency of gene transfer. This resulted in a greater number of genetically corrected stem cells capable of stable engraftment and sustained production of functional hemoglobin.

The new study (BTHAL-FT007-01) will be conducted at IRCCS Ospedale San Raffaele and Bambino Gesù Children's Hospital, which previously coordinated Italy's gene-editing treatment protocol. The trial will enroll nine patients between the ages of 3 and 35 years.

The first phase will involve three adult patients. Following an independent evaluation of safety and efficacy data, enrollment will be expanded to include six additional participants, including children and adolescents.

Stem cells will be collected at the participating clinical centers, while the investigational medicinal product will be manufactured centrally at the Advanced Therapy Manufacturing Facility of Bambino Gesù Children's Hospital.

Producing the therapy within an academic setting is one of the project's defining features and reflects the collaboration between Fondazione Telethon, the Process Development Lab at SR-Tiget, and the Advanced Therapy Manufacturing Facility at OPBG.

The project has also received funding through Italy's National Recovery and Resilience Plan (PNRR), specifically within the RNA & Gene Therapy National Research Center (Mission M4C2, Spoke 10: Pre-clinical Development, GMP Manufacturing and Clinical Trials of Gene Therapy Medicinal Products).

The primary objective of the study is to determine whether the therapy enables patients to achieve transfusion independence, defined as no need for blood transfusions for at least 12 consecutive months after treatment. Researchers will also assess:

• treatment safety;
• successful engraftment of genetically corrected stem cells;
• reduction of iron overload;
• overall quality of life for patients and their families.

Participants will be monitored for two years following treatment and will then enter the long-term follow-up program required for advanced therapies, allowing researchers to continue evaluating safety and effectiveness for up to 15 years after infusion.

Giuliana Ferrari, Head of the Stem Cell Gene Transfer Unit at SR-Tiget and Professor of Molecular Biology at Vita-Salute San Raffaele University, commented:

"Every clinical trial is built upon years of research. In this project, we focused on overcoming one of the key limitations identified in previous studies—the proportion and quality of genetically corrected stem cells capable of stable engraftment. Shortening the culture time of hematopoietic stem cells helps preserve the biological properties essential for successful engraftment and long-term restoration of blood cell production after transplantation. At the same time, introducing specific transduction enhancers improves the efficiency of therapeutic gene transfer. The results achieved so far give us confidence in the potential of this new approach."

Alessandro Aiuti, Deputy Director of SR-Tiget, Head of the Pediatric Immunohematology Clinical Unit at IRCCS Ospedale San Raffaele, Professor of Pediatrics at Vita-Salute San Raffaele University, and Principal Investigator of the study at OSR, added:

"The pilot study demonstrated that gene therapy can provide long-lasting benefits for patients with transfusion-dependent beta-thalassemia. It also showed that the magnitude of this benefit depends on the ability of genetically corrected stem cells to successfully engraft in the bone marrow.

This new protocol was specifically designed to address that challenge. Our goal is to increase the number of corrected cells contributing to hemoglobin production, thereby improving the chances of achieving transfusion independence while maintaining the favorable safety profile observed to date."

Franco Locatelli, Director of the Clinical Department of Pediatric Hematology and Oncology, Cell Therapy, Gene Therapy and Hematopoietic Stem Cell Transplantation at Bambino Gesù Children's Hospital, and Principal Investigator of the study at OPBG, stated:

"It is essential to continue developing new therapeutic options for patients with transfusion-dependent beta-thalassemia who currently have limited access to potentially curative treatments.

This study may provide an additional future treatment option for patients who are not eligible for other innovative therapies. Furthermore, developing and manufacturing these advanced therapies within academic institutions is a crucial step toward improving both the sustainability and accessibility of cutting-edge treatments."

For any questions or requests for information regarding the investigational gene therapy described above, please contact scientificservice@fondazionetelethon.it directly.