Ten children born without immune defenses and therefore exposed to all infections, without natural shields or protections, have been living healthy for months, if not years, without signs of disease. The credit goes to gene therapy, the technology that has made it possible to engineer the stem cells of children and to insert a functioning copy of the gene that was defective in them. This is what the researchers at the University of California of San Francisco who are treating them write on the pages of the New England Journal of Medicine.
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The children were born with Artemis-SCID, a rare genetic disease characterized by the absence of T and B lymphocytes, which is usually treated with a donor bone marrow transplant, ideally a matching brother or sister. “But this form of severe combined immunodeficiency carries a higher risk that the transplant will fail. There was therefore a need for a new therapy, to be carried out in an autologous context, which uses the same genetically modified cells of the patient”, explains Maria Pia Cicalese, doctor and researcher at the San Raffaele Telethon Institute for Gene Therapy in Milan , where the first gene therapy approved as a drug for another form of severe combined immunodeficiency, ADA-SCID, was born.
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The children are fine
The technique used in California is partly the result of that developed in the Milanese laboratories, but more up-to-date. Babies have been identified largely through newborn screening and therefore treated very early. “They underwent marrow explantation in the first months of life, their cells were purified to extrapolate the real stem cells which were then genetically corrected using a lentivirus – a new generation vector – so as to express the corrected gene instead of the mutated one ”, explains Cicalese again. “At this point, before the cells are reinfused into the patients, they are given low-dose chemotherapy to make room in their marrow for the new genetically corrected cells.”
Today the children, who are all under the age of 5, are doing well and living at home with their families, attending school, playing and living normal lives. “In them the course of the disease is much better than with standard treatment. I’ve never seen results like this. It’s amazing,” says Mort Cowan, a pediatrician who led the research team. The first objective of the study was to demonstrate the safety of infusing the correct cells which began to differentiate after about forty days. The second goal was that of rebuilding the immune system, measured after 12 months. In all 10 patients the cells differentiated and only one had to undergo a second infusion of gene therapy. Among the evaluable children, because they had been infused for a sufficient number of months to be able to draw conclusions, 4 achieved complete reconstruction of the T lymphocyte population after 12 months, and 4 after 24 months also of the B lymphocytes. have achieved complete immunity T is truly remarkable. B lymphocytes take longer to settle, but data show that there is a higher chance of this occurring in these patients than in those receiving a bone marrow transplant,” explains Jennifer Puck, co-author of the study with Cowan.
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The process of becoming a drug
Compared to the technique used for ADA-SCID, the American researchers used a different vector to ferry the corrected gene into the cells, but above all they froze the cells after modifying them and thawed them before infusing them into the patients. With a process that can be more easily industrialized, when and if a company will want to invest in the development of a drug. “The problem of economic sustainability, in fact, has a significant impact on the possibility of making these therapies available to all those who need them”, underlines Cicalese. Children suffering from ADA-SCID and those suffering from metachromatic leukodystrophy, another rare genetic disease for which Telethon has developed a gene therapy, know something about it. Both therapies were developed and brought to the market thanks to the investment of a pharmaceutical company which has now, however, divested itself of the package of gene therapies for primitive immunodeficiencies, because going ahead is too expensive. The consequences were also paid by the therapy for another immunodeficiency, the Wiskott-Aldrich syndrome: the dossier for submission to the regulatory agencies was ready to be presented but now everything is at a standstill. “Fondazione Telethon has decided to acquire from Orchad Therapeutics the license to complete the market authorization process in this case and that of the already approved ADA SCID therapy, to make them available to patients”, concludes Cicalese. “Faced with the problems of sustainability posed by these therapies, the importance of the role that academies can play, even jointly, in carrying out projects that companies do not have the will to continue for reasons of high cost of therapies and rarity of the conditions themselves”.