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Giuliana Ferrari, PhD - "Gene therapy for beta-thalassemia: the long road from the bench to the bedside"

SR-TIGET and Vita-Salute San Raffaele University Medical School, Milan, Italy
When Jun 04, 2019
from 03:00 PM to 04:00 PM
Where Tigem, Vesuvius Auditorium
Contact Name
Contact Phone 081-19230659
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Short CV

ß-thalassemia is a congenital anemia and one of the most common monogenic disorders associated to morbidity and mortality. The molecular basis of β-thalassemia are point mutations or deletions in HBB gene resulting in a reduction (ß+ genotype) or complete elimination (ß0 genotype) of ß-chains from adult hemoglobin (HbA), chains imbalance with excess of α-chains, and consequently ineffective erythropoiesis. Homozygosity of β-thalassemia mutations results in a disease phenotype with varying severity, depending on the type of mutations and other modifying factors, from mild forms of anemia to severe anemia referred to as β-thalassemia major. In addition to chronic hemolytic anemia, patients affected by β-thalassemia major show disease hallmarks as compensatory hematopoietic expansion in bone marrow cavities, often resulting in bone deformities, and in ectopic sites, hypercoagulability and increased intestinal iron adsorption. The conventional management for patients affected by the severe forms of the disease relies on chronic and regular blood transfusions in association to iron-chelation therapy. At present, the only curative approach is represented by allogeneic hematopoietic stem cell transplantation, with a probability to find a well-matched donor of <25%.
Ex vivo gene therapy, using autologous genetically modified hematopoietic stem cells (HSC), potentially represents a cure applicable to all patients regardless of donor availability and free from transplant related immunological complications such as graft rejection and graft-versus-host-disease. The development and large scale production of clinical grade HIV-derived lentiviral vectors expressing human ß-globin, and the optimization of gene transfer protocols in HSCs have progressed this field to the pioneering clinical trials in France and in U.S.A., and more recently in Italy. The first results of clinical benefit, including early engraftment, hemoglobin expression and transfusion independence were reported for some patients and are proving the potential efficacy of this therapeutic approach.
Although these encouraging results, early clinical studies showed the safety and potential efficacy of this therapeutic approach, as well as the hurdles still limiting its general application. These are the nature and source of hematopoietic stem cells, the suboptimal transduction efficiency and gene expression levels, the toxicity and efficacy of bone marrow conditioning, the level of engraftment of genetically modified long-term HSC and the potential impact of an altered bone marrow microenvironment on stem cell harvesting as well as engraftment.
Our contribution to this field in the last 10 years was devoted to the clinical development of a safe gene therapy approach for ß-thalassemia using the GLOBE lentiviral vector. The crucial steps leading to TIGET BTHAL clinical trial, as well as preliminary data on treated patients, will be presented.

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