Fondazione Telethon and IRCCS Ospedale San Raffaele, sponsors of the trial, together with Ospedale Pediatrico Bambino Gesù launch a multicenter study based on an optimized gene therapy protocol developed at the SR-Tiget Institute.
A Phase IIb gene therapy clinical trial for patients with transfusion-dependent beta-thalassemia has been launched at IRCCS Ospedale San Raffaele (OSR) in Milan and Ospedale Pediatrico Bambino Gesù (OPBG) in Rome. The study is sponsored by Fondazione Telethon and Ospedale San Raffaele. Its goal is to evaluate the safety and efficacy profile of an optimized version of the approach developed at the San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget) in Milan, which has already been investigated in a previous trial.
What is beta-thalassemia
Beta-thalassemia is an inherited genetic blood disorder caused by reduced or absent production of the beta-globin chains of hemoglobin, a protein essential for transporting oxygen to tissues. People with transfusion-dependent forms must undergo regular lifelong transfusions and continuous treatments to counter iron overload. Over time, although life-saving, transfusion therapy can damage multiple organs due to iron accumulation and may therefore limit quality of life.
Currently, hematopoietic stem cell transplantation from a compatible donor is a potentially curative option, but it is feasible only for a minority of patients and is associated with significant risks. A therapy based on gene-edited hematopoietic stem cells has also recently become available in Italy for specific patient groups. However, advanced therapies already approved for beta-thalassemia still present limitations related to patient age, genetic characteristics, or treatment availability.
The clinical trial
The new protocol represents the evolution of a pilot clinical study launched in 2015 by Fondazione Telethon and OSR (NCT02453477), which involved correcting patients’ hematopoietic stem cells using a lentiviral vector. In that trial, some patients achieved reduced transfusion needs and, in some cases, long-term transfusion independence (see Marktel et al, Nature Medicine 2019).
Based on those results, SR-Tiget researchers optimized the cell preparation process by reducing culture time and increasing gene correction efficiency, resulting in a higher number of corrected cells capable of stable engraftment and long-lasting production of functional hemoglobin.
The new study (BTHAL-FT007-01) will be conducted at OSR and OPBG—an institution that has already coordinated a gene-editing treatment protocol—and will involve a total of nine patients aged 3 to 35 years. Initially, three adult patients will be treated; subsequently, following an independent evaluation of safety and efficacy data, the treatment will be extended to six additional patients, including children and adolescents.
A strong academic collaboration
Stem cells will be collected at participating clinical centers, while centralized manufacturing of the investigational medicinal product will take place at the OPBG Pharmaceutical Facility dedicated to advanced therapies. Producing the therapy in an academic setting is a distinctive feature of the project and results from collaboration among Fondazione Telethon, the SR-Tiget Process Development Lab, and OPBG’s Pharmaceutical Facility. The project has benefitted from funding under the Italian National Recovery and Resilience Plan (PNRR), particularly within the RNA & Gene Therapy National Research Center (area M4C2, Spoke 10 “Pre-clinical Development, GMP Manufacturing and Clinical Trials of GTMP”).
Assessing transfusion independence and expanding treatment options
The study will assess whether the therapy can achieve transfusion independence, defined as no need for transfusions for at least 12 consecutive months after infusion. It will also evaluate treatment safety, engraftment of genetically corrected cells, reduction of iron overload, and overall quality of life for patients and their families.
Participants will be monitored for two years after treatment and then enrolled in a long-term follow-up program, as required for advanced therapies, allowing continued evaluation of safety and efficacy for up to 15 years post-infusion.
Giuliana Ferrari, Head of the Hemoglobinopathies Gene Therapy Development Unit at SR-Tiget and Full Professor of Molecular Biology at the Vita-Salute San Raffaele University:
“Behind every clinical trial there is always a long research effort. In this case, we worked to overcome one of the limitations observed in previous studies, namely the percentage and quality of genetically corrected cells capable of stable engraftment. Reducing the culture time of hematopoietic stem cells helps preserve their essential properties for engraftment and hematopoietic reconstitution after transplantation, while introducing specific transduction enhancers increases the efficiency of therapeutic gene transfer. The results obtained so far give us confidence in the potential of this new approach.”
Alessandro Aiuti, Deputy Director of SR-Tiget, Full Professor of Pediatrics at Vita-Salute San Raffaele University and principal investigator of the trial at OSR: “The pilot study demonstrated that gene therapy can offer lasting benefit to patients with transfusion-dependent beta-thalassemia, but also highlighted how this benefit depends on the ability of genetically corrected cells to stably engraft in the bone marrow. The new protocol was designed precisely to address this challenge: the goal is to increase the number of corrected cells contributing to hemoglobin production and thus improve the chances of achieving transfusion independence, while maintaining the favorable safety profile observed so far.”
Franco Locatelli, Head of the Clinical Area of Oncohematology, Cell and Gene Therapy and Hematopoietic Transplantation at OPBG, Full Professor of Pediatrics at Catholic University of the Sacred Heart and and principal investigator of the trial at OPBG: “It is essential to continue developing new therapeutic options for patients with transfusion-dependent thalassemia who may not currently have access to potentially curative approaches. This study may offer an additional future therapeutic opportunity also for patients who do not yet have access to other innovative strategies. Furthermore, developing and manufacturing these therapies in an academic setting is an important factor in improving sustainability and accessibility of advanced care.”
Any questions or requests for information regarding the aforementioned therapy currently in development should be sent directly to scientificservice@fondazionetelethon.it .
