Beta Thalassemia: encouraging evidence for safety and efficacy of gene therapy

Gene therapy, especially if administered early in life, could be an effective treatment for beta thalassemia, a genetic disease that is widespread in Mediterranean countries, affecting over 7000 patients in Italy only. These are the results – published in Nature Medicine – of the first clinical trial of gene therapy for beta thalassemia involving both adult and paediatric patients.

This clinical trial is the result of more than ten years of preclinical research performed by the group led by Giuliana Ferrari, professor at Università Vita Salute-San Raffaele, at the San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget) in Milan and made possible by the strategic alliance between IRCCS San Raffaele Hospital, Fondazione Telethon and Orchard Therapeutics. The study was the result of the synergy between basic researchers and clinicians, and in collaboration with the Pediatric Immunohematology Unit headed by Alessandro Aiuti, the Hematology and Hematopoietic Stem Cell Transplantation Unit headed by Fabio Ciceri, and the Rare Disease Center of Policlinico headed by Maria Domenica Cappellini. The study, with the clinical coordination of doctor Sarah Marktel, has involved other Italian centers specialized in thalassemia and the cooperation of patient organizations.


Team FerrariTeam Ferrari

Giuliana Ferrari and her lab members at SR-Tiget

Beta thalassaemia is a genetic blood disorder caused by a mutation in the gene coding for beta-globin, a component of haemoglobin protein, essential for the functioning of red blood cells and in particular for oxygen transportation.

There are more than 300 known mutations of the gene, which give rise to different forms of beta thalassaemia, of varying severity. The most severe mutations cause an almost complete absence of the protein in the blood of patients, who have to resort to frequent transfusions to survive – resulting in a dramatic reduction of their quality of life – or to bone marrow transplantation from a compatible donor.



The study involved nine subjects of different ages – three adults over 30 years old, three adolescents and three children under six years old – all with transfusion-dependent beta thalassaemia. The researchers used a gene therapy technique similar to that already used for other rare blood diseases, such as ADA-SCID (whose treatment became the world's first approved life-saving gene therapy drug), Metachromatic Leukodystrophy (MLD) and Wiskott-Aldrich Syndrome (WAS).

The first phase of the protocol consists in collecting hematopoietic stem cells from patients' peripheral blood. To restore the proper function of these cells and the red blood cells they differentiate into, the researchers insert a functioning copy of the beta-globin gene using a lentiviral vector (a virus from the same family as HIV, emptied of its infectious content and transformed into a shuttle for therapy). Finally, the corrected stem cells are re-infused into patients' bones, so that they could rapidly reach the bone marrow.

Over one year later (adult patients were treated first, almost 3 years ago) the treatment provides encouraging evidence of being safe and effective: 3 out of 4 younger patients with a long enough follow-up period to be evaluated don’t require blood transfusions at all, while the three adult patients now require significantly less transfusion. Only one of the treated children did not show any positive effect on the progression of the disease and the researchers are now trying to find out why.

"This is the first time that gene therapy for beta-thalassaemia has been used in paediatric patients. Since the disease progressively compromises the integrity of the bone marrow, intervening at a young age gives better results," explains Giuliana Ferrari. "In addition to the age factor, another key element is the efficiency of gene transfer: the ability of the viral vector of actually inserting successfully the therapeutic gene inside the patient’s cells. In complex diseases such as beta-thalassaemia, this can play an important role, which is why the development of innovative protocols that will maximise gene transfer efficiency is one of our priorities” concludes Giuliana Ferrari.