• Gene therapy has been shown to preserve motor function and cognitive abilities in the majority of patients, provided it is administered early: therefore, newborn screening would be essential to diagnose the disease early, but the test is not yet uniformly available either in Italy or globally.
• Most patients treated before the disease manifested itself are able to walk and have a cognitive development in line with healthy children.
• The study was conducted at Ospedale San Raffaele in Milan and is the result of more than 20 years of research by the San Raffaele-Telethon Institute for Gene Therapy and the commitment of Fondazione Telethon to transforming research into therapies available for patients.

Milan, 24 April 2025 – If administered early, gene therapy has the potential to change the medical history of children born with metachromatic leukodystrophy (MLD), a rare and lethal neurodegenerative disease of genetic origin which leads to the progressive loss of the ability to walk, talk and interact. This was confirmed by a study published in the New England Journal of Medicine[1] which showed that the therapy, if administered early, is able to preserve motor function and cognitive abilities in most patients.

The study was conducted on 39 children with MLD at the San Raffaele Hospital in Milan by clinical researchers Francesca Fumagalli and Valeria Calbi, under the coordination of Alessandro Aiuti, vice-director of the San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget), head of the Paediatric Immunohaematology Operating Unit at the IRCCS San Raffaele Hospital in Milan and full professor of Paediatrics at the Vita-Salute San Raffaele University. This therapy was approved in the EU in 2020 and has been available and reimbursed in Italy since 2022: it is the result of more than 20 years of research conducted at SR-Tiget and of the strategic alliance between Fondazione Telethon and Ospedale San Raffaele with the anglo-american company Orchard Therapeutics, which holds the licence both in the EU and in the US.

The results of the study

In the course of the study, patients with MLD were treated with gene therapy based on genetically corrected haematopoietic stem cells and the results were then compared with those of 49 untreated patients. Among the key indicators to assess the effectiveness of the therapy, the researchers considered the impact on motor skills (ability to walk or sit unsupported), cognitive skills (ability to speak or perform specific tests) and survival more generally.

The study confirmed that even in the long term, gene therapy can significantly reduce the risk of severe motor and cognitive impairment in all subgroups of patients treated: those with the late-infantile form, in which the onset of symptoms is expected between 6 months and 2½ years, those with the early-juvenile form, in which the onset is expected between 2½ and 6 years, treated in the pre-symptomatic phase of the disease, and early-juvenile patients treated in the presence of mild symptoms, albeit with less efficacy than for motor symptoms.

As the study’s first authors Francesca Fumagalli and Valeria Calbi explain, ‘Most of the children treated before the onset of symptoms retained their ability to walk, whereas this was lost in the first years of life in all the children in the control group, who had not received gene therapy because they were already symptomatic or because they had been diagnosed when the therapy was not yet available. In many cases, these were the older brothers or sisters of the children who then received the treatment and who made it possible to diagnose the disease in their younger siblings: we would like to emphasize the generosity of the families of these patients, because without them we would not have been able to know the natural progression of the disease over time so well and to better evaluate the effects of the therapy. As far as cognitive development is concerned, we have observed a significant benefit in almost all treated patients, who continue to acquire new cognitive skills compared to the control group with severe cognitive impairment and loss of all ability to communicate’.

In the light of these data collected over 12 years, which confirm that the positive effects of gene therapy are maintained over time, it becomes a priority to diagnose the disease early so as to maximize the effectiveness of treatment. “Thanks to research, we have a therapy available that can change the course of a serious and unfortunately fatal disease without intervention, but only effective if acted upon in time. This is why it is essential to have a newborn screening test for MLD as soon as possible, in order to diagnose the disease when it has not yet manifested itself,’ said Alessandro Aiuti. A delay in diagnosis can, in fact, irretrievably preclude the possibility of intervening with gene therapy. Often the diagnosis comes too late, or ‘thanks’ to an older brother or sister who has already been diagnosed and cannot be treated’.

What is metachromatic leukodystrophy

Metachromatic leukodystrophy (MLD) is caused by mutations in a gene responsible for the metabolism of particular substances called sulfatides, which, if not disposed of properly accumulate particularly in the central and peripheral nervous system. In the most severe forms, these children rapidly lose the ability to walk, talk and interact with the world around them: most of them die in infancy and have only palliative care available to them. It is estimated that 1 in every 100,000 children globally is born with this disease every year.

Gene therapy

It is administered via a single infusion after chemotherapy to make room for the correct cells and is approved in the EU and the US. It is indicated for children with the late-infantile or juvenile-early-onset forms who have not yet manifested clinical signs of the disease, and for those with the juvenile-early-onset form who, although presenting the first clinical manifestations, are still able to walk independently and have not yet shown a decline in cognitive abilities.

Newborn screening for MLD

Newborn screening is a simple, non-invasive test and is one of the main public preventive medicine programmes. By means of a test carried out on a blood sample taken from the heel of each newborn baby during the first three days of life, it makes it possible to identify at an early stage a number of genetic metabolic diseases on which dietary or pharmacological treatment can be applied. In Italy, thanks to Law 167, since 2016 this test has been extended nationwide to more than 40 diseases: according to the Italian Society for the Study of Metabolic Hereditary Diseases and Neonatal Screening (SIMMESN), approximately 350 Italian children who could receive a life-saving diagnosis each year.

MLD is currently not among the diseases subject to newborn screening, neither in Italy nor in the rest of the world (only Norway is an exception). However, more than a dozen pilot studies are underway, two of which are in Italy: one started in March 2023 in Tuscany, coordinated by the AOU Meyer IRCCS in Florence and financed also thanks to the Voa Voa Amici di Sofia Association, and one started in July 2024 in Lombardy, promoted by Fondazione Telethon thanks to an agreement with the Buzzi Children’s Hospital Foundation and coordinated by the ‘Vittore Buzzi’ Children’s Hospital in Milan (currently available in 17 of the 72 birth points in Lombardy) .

To date, in the context of these pilot studies, it has been possible to diagnose MLD early in four children, three in Germany[2] and one in the United Kingdom[3] , who were offered the opportunity of gene therapy at an early stage. As far as the Italian studies are concerned, to date none of the approximately 50,000 babies screened in Tuscany and Lombardy has tested positive.

Fondazione Telethon ETS is one of the main Italian biomedical charities, founded in 1990 on the initiative of a group of patients suffering from muscular dystrophy. Its mission is to achieve the cure of rare genetic diseases through scientific research of excellence, selected according to the best practices shared internationally. Through a unique method, it follows the entire “research chain” dealing with fundraising, selection and funding of projects and the research activity itself carried out in the centers and laboratories of the Foundation.  

Fondazione Telethon also develops collaborations with public health institutions and pharmaceutical industries to translate the results of research into therapies accessible to patients. Since its foundation, Fondazione Telethon has invested 698 million euros in research, has funded 3,024 projects with 1,771 researchers involved and 637 diseases studied.  

To date, thanks to advance research of Fondazione Telethon and in collaboration with the pharmaceutical industry, the first gene therapy with stem cells in the world has been made available. This therapy is intended for the treatment of ADA-SCID, a severe immunodeficiency that compromises the body’s defences from birth. In 2023, Fondazione Telethon became responsible for its production and distribution to eligible patients in the European Union. Another gene therapy resulting from Fondazione Telethon research made available is intended for the treatment of a serious neurodegenerative disease, metachromatic leukodystrophy. These may soon be joined by gene therapy for another immunodeficiency, Wiskott-Aldrich syndrome, for which the Foundation in addition to research is also supporting the approval process.  

Other diseases on which the gene therapy developed by Fondazione Telethon researchers has been evaluated in patients are Beta Thalassemia, Mucopolysaccharidosis type 6 and type 1 and Usher Syndrome, type 1b. In addition, within the Fondazione Telethon institutes a targeted therapeutic strategy is being studied or developed for other genetic diseases, such as haemophilia or various hereditary vision defects. In parallel, the study of basic mechanisms and potential therapeutic approaches for diseases still unanswered continues in all laboratories funded by Fondazione Telethon. 

Ospedale San Raffaele (OSR) is a clinical-scientific-university facility of international importance and high specialisation for several important pathologies, inaugurated in 1971 and recognised in 1972 as an Institute for Hospitalisation and Scientific Care (IRCCS). It is a Highly Specialised Emergency Centre (E.A.S.) and the teaching-assistance centre of the Vita-Salute San Raffaele University. In May 2012 San Raffaele became part of the San Donato Group, Italy’s leading private hospital group, which has 18 hospitals including 3 IRCCSs. IRCCS Ospedale San Raffaele is a polyclinic accredited with the National Health Service with over 60 clinical specialities. The multidisciplinary structure, technologically advanced, and the continuous interaction between scientific research, teaching and clinical activities have allowed IRCCS Ospedale San Raffaele to achieve such results over the years that it has been placed at the top of the Italian rankings for scientific productivity and a point of reference in Europe and globally for the study and treatment of many pathologies and for the development of innovative therapies.

Università Vita-Salute San Raffaele (UniSR) is a university of excellence inaugurated in 1996 and internationally recognised for the high quality of its research and teaching. With over 5,700 enrolled students, UniSR offers bachelor’s and master’s degree courses, speciality schools, postgraduate master’s degrees and doctoral programmes. Since its inception, the University has been characterised by a strong integration between biomedical, socio-psychological and philosophical research, in the conviction that the improvement of the human condition cannot disregard any of these three dimensions. UniSR’s biomedical research activity – translational and high-tech – is conducted in synergy with IRCCS Ospedale San Raffaele, one of the most important research hospitals in the country.

[1] N Engl J Med 2025;392:1609-20. DOI: 10.1056/NEJMoa2405727. Long-Term Effects of Atidarsagene Autotemcel

for Metachromatic Leukodystrophy

[2] N Engl J Med. 2024 Oct 3;391(13):1256-1258. doi: 10.1056/NEJMc2407165. Epub 2024 Sep 18. Newborn Screening and Presymptomatic Treatment of Metachromatic Leukodystrophy

[3] Mol Genet Metab. 2024 May;142(1):108349. doi: 10.1016/j.ymgme.2024.108349. Epub 2024 Feb 20. Improving newborn screening test performance for metachromatic leukodystrophy: Recommendation from a pre-pilot study that identified a late-infantile case for treatment