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Giuliana Ferrari, San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET) Milan, Italy. 2010.

Gene therapy of genetic diseases affecting the hematopoietic system is based on the transplantation of a patient’s own bone marrow cells that have been corrected by inserting a new copy of a normal gene. In the case of severe thalassaemia, transplantation of autologous hematopoietic cells, genetically corrected to express normal level of haemoglobin, would provide the advantage over the conventional transplantation to cure virtually all patients, without donor limitation and reducing the risk of rejection or graft-versus-host disease associated with allogeneic transplantation.

In order to drive a functional ß-globin gene in the cells, we need a shuttle, named the vector, which is derived by a modified virus no longer dangerous. Recently, new vectors were developed which are able to transfer with high efficiency genes in hematopoietic stem cells. The procedure of gene therapy implies the following steps:
- development and production of the vector
- harvest of hematopoietic stem cells from the patient
- gene transfer of ß-globin gene by the vector into the cells
- treatment of the patient to reduce the erythroid mass and to allow engraftment of the transplanted cells in the bone marrow
- transplantation of genetically corrected cells to the patient
Several investigators have been intensively working in the field of gene therapy for thalassaemia in U.S.A (Michel Sadelain, Philippe Leboulch, Punam Malik, Derek Persons) and in Italy (Giuliana Ferrari) and the results demonstrate feasibility and efficacy in preclinical models. Now, the results from one patient treated in France by Philippe Leboulch and collaborators in the first clinical trial are available and show potential and limitation of gene therapy (M.Cavazzana-Calvo et al., Nature 467, September 16th 2010).

In 2007, an 18-year-old male patient affected by HbE/ß-thalassaemia was transplanted with his genetically modified bone marrow cells. In this type of patients one mutated allele is able to produce an Hb variant, called HbE, but the compound heterozygous state (ßE/ß0) leads to thalassaemia major. A functional ß-globin gene was inserted in patient’s cells using as shuttle a modified virus derived by HIV (lentiviral vector). The vector is able to enter in the cell DNA and deliver the new globin gene in between the other genes of the cell. Before administering his genetically corrected cells, the patient was treated with chemotherapy to make space for the incoming transplanted cells. After 3 years, the patient is transfusion independent, with a level of 9-10g/dl Hb. The genetically modified cells represent only a fraction of the total bone marrow cells (11%) but they are able to give rise to healthy blood cells, producing 1/3 of the total haemoglobin (3.7g/dl). Concomitantly, the discontinuation of transfusion led to the rising of HbE and HbF, which contribute to the 2/3 of total Hb, raising the level to 9-10g/dl. This is an encouraging result proving the efficacy of gene therapy in patients requiring a limited contribution from vector-derived Hb, like in the case of ßE/ß0-thalassemia.

On the other hand, this result was obtained in the presence of a small amount of cells repopulating the patient’s bone marrow after chemotherapy. Among them, one is predominant, carrying specific vector integration in a gene called HMG2A. The predominance of this clone can be due to the effect of vector integration in that particular gene and/or to the poor content of repopulating cells in the transplant, favouring the expansion of cells endowed with the best survival potential. The monitoring of the patient’s state will give the final answer in term of safety.

At the same time, the preclinical evaluation of gene therapy with a lentiviral vector for ß-globin, called GLOBE, was conducted in Italy (by the group of Giuliana Ferrari) on a large number of patients’ samples (Roselle et al., EMBO Molded 2, 315, 2010). The results of this extensive work can be summarized in the following points:
a) the gene transfer procedure does not adversely impact the functional capacity of bone marrow cells;
b) the GLOBE vector is able to correct ß-globin deficiency at low copy number of integrations;
c) The vector integrates everywhere in the DNA, without favouring dangerous genes.
Therefore, utilizing the right preclinical models we can make a good prediction of safety, although the final answer will come only from treating patients. Currently, the Italian group is completing all the tests required for clinical application of the vector in gene therapy.
Finally, we can foresee that in the next future new trials for thalassaemia will start and from the upcoming results we will learn the best way to treat thalassaemia by gene therapy.

References:

1. Cavazzana-Calvo et al. “Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia”. Nature 2010 467(7313):277-8.
2. Roselli et al. “Correction of beta-thalassemia major by gene transfer in haematopoietic progenitors of pediatric patients.” Comment in EMBO Mol Med. 2010 2(8):291-3.

This page was last updated October 2010 by Dr Michael Angastiniotis, MD, DCH (Paediatrician)