Twenty-nine little patients made it: thanks to gene therapy their cognitive and motor development was similar to that of healthy children. They are patients suffering from metachromatic leukodystrophy (Mld), a rare neurodegenerative disease of genetic origin. Thanks to the experimentation conducted on this group of patients, it was possible to see concretely how gene therapy can change their clinical history. The results of this long-term study, the fruit of over 20 years of research conducted at the San Raffaele Telethon Institute for Gene Therapy in Milan, were recently published in the prestigious journal The Lancet.
Research
The study, conducted thanks to the strategic alliance between the Telethon Foundation, IRCCS San Raffaele Hospital and Orchard Therapeutics and the collaboration of other Italian hospitals and institutes, including the University of Perugia for biochemical analyzes, is the first in the long term on gene therapy for metachromatic leukodystrophy. It includes 29 patients and demonstrates the efficacy and safety of the first gene therapy drug for this disease, approved by the European Commission in December 2020 in preventing severe disability in these children. The study – coordinated by Professor Alessandro Aiuti, deputy director of SR-Tiget and full professor of pediatrics at the Vita-Salute San Raffaele University in Milan – suggests the importance of intervening early: most patients have been treated before that the disease manifested itself and showed physical and cognitive development in line with those of healthy children.
The results
Doctors and researchers used multiple indicators, both molecular and clinical, to measure the success of the treatment: first of all, the level of engraftment of the modified cells in the patients’ bone marrow and the quantity of enzyme present in the cerebrospinal fluid; but also the development of the central nervous system – monitored by magnetic resonance imaging – and the evolution of the cognitive and motor skills of children, evaluated through standardized clinical tests. “Out of 29 treated patients, 25 had a path of both physical and cognitive development similar to that of healthy children or showed a slowdown in the progression of damage compared to what was expected. The therapy proved to be well tolerated and the side effects the most important were linked to the chemotherapy treatment that precedes the infusion of the corrected cells “, say Francesca Fumagalli and Valeria Calbi, respectively neurologist and hematologist at the Clinical Research Unit of SR-Tiget and first authors of the study.
The importance of timely intervention
Unfortunately, two treated patients – whose symptoms had manifested before the administration of the therapy – died due to the progression of the disease. “The results of the clinical study underline the importance of intervening as soon as possible: it takes a few months, after the infusion of the correct cells, for the levels of the ARSA enzyme to return to normal. The therapy can in fact prevent degeneration of the nervous system. or slow it down if administered in the earliest stages, but it cannot be remedied if the disease is already rapidly progressing, “the two researchers conclude.
The importance of newborn screening
Neonatal screening is a simple and non-invasive test: it consists of a blood sample taken from the baby’s heel and allows the recognition of over 40 genetic metabolic diseases for which today we have a targeted response. The test is free and is done directly in the hospital within 72 hours of birth. Unfortunately, the responsible alteration of Mld is not yet part of the test in Italy. “Now that effective therapy is available for metachromatic leukodystrophy, it will be essential to start birth screening programs for this disease as soon as possible,” said Alessandro Aiuti, study coordinator. “In the absence of a newborn screening test, it is impossible to know that the disease is present before it manifests – when, that is, it is often too late – unless there is an older brother or sister who has already been diagnosed. And this is the biggest regret: the fact that for every child we have been able to successfully treat before symptoms appear, and who can potentially have a full-fledged normal life, there is a brother or sister older than they have been able to benefit from it. Newborn screening can change all of that. “
How does gene therapy work for Mld
Metachromatic leukodystrophy is a rare metabolic disease with approximately one case in every 100,000 new births. It is caused by mutations in a gene called ARSA, which codes for a key enzyme in the elimination of sulfatides. In children with the most severe forms of the disease, the enzyme is not present or does not work and sulfatides accumulate in several organs, including the central and peripheral nervous systems, leading to rapid neurodegeneration and loss of key motor and cognitive functions. . Gene therapy based on modified blood stem cells works by correcting cells taken from patients through inactivated lentiviral vectors. The vectors insert functioning copies of the ARSA gene into the cells and these are then infused back into the patient, where once they have taken root they pass the therapeutic gene to subsequent generations of cells. “One of the fundamental characteristics of this therapy is that the genetically modified cells, once infused into the patient and taken root in the tissues, do not limit themselves to producing the missing enzyme, but are able to distribute it to the surrounding cells which are thus corrected in their metabolic defect. . This allows the therapeutic benefit to be distributed in the patient’s tissues, including the nervous system, and thus to prevent their degeneration, provided that action is taken early “explains Alessandra Biffi, full professor of pediatrics and director of the pediatric oncohematology division of the University degli Studi di Padova, who together with Professor Luigi Naldini, director of SR-Tiget, contributed to the original development of the therapy.