2023-06-28 17:27:00
An international study with a strong Italian presence has discovered the first genetic variant associated with a more rapid progression of multiple sclerosis (MS). “Inheriting it from both parents accelerates the time to needing a walking aid by almost 4 years,” explains Sergio Baranzini, professor of Neurology at the University of California at San Francisco (UCSF), USA, co-senior author of the work published in ‘Nature’, the result of collaboration between more than 70 institutions worldwide led by UCSF and the University of Cambridge, UK. The research, conducted on over 22,000 patients, therefore identifies the first genetic marker of serious pathology and ignites new hopes. “Understanding how the variant affects MS severity will hopefully pave the way for a new generation of treatments that can prevent disease progression,” says Stephen Sawcer, a professor at the University of Cambridge, another co-senior author.
Multiple sclerosis is the result of the immune system mistakenly attacking the brain and spinal cord causing flare-ups of symptoms, known as relapses, and long-term degeneration, known as progression, a buildup of disability, the university recalls. State University of Milan which for Italy collaborated on the study together with the universities of Eastern Piedmont, the Irccs San Raffaele hospital in Milan, the Irccs Casa Sollievo della Sofferenza Foundation in San Giovanni Rotondo (Foggia) and Asst Santi Paolo e Carlo in Milan. Despite the development of effective treatments for relapses, none can reliably prevent the accumulation of disabilities. Previous research has shown that susceptibility or risk of MS results largely from immune system dysfunctions and that some of these dysfunctions can be treated, slowing down the disease. But “these risk factors – Baranzini points out – do not explain why, 10 years after diagnosis, some people with MS are in wheelchairs while others continue to run marathons”.
To shed light on the mystery, the International Multiple Sclerosis Genetics Consortium (IMSGC) and the MultipleMs Consortium have joined forces. The two consortia have integrated data from more than 12,000 MS patients to complete a genome-wide association study (GWAS), which uses statistics to accurately associate genetic variants with particular traits in this case related to MS severity, including for example the years it takes for each patient to go from diagnosis to a certain level of disability. After sifting through more than 7 million genetic variants, researchers found one associated with faster disease progression. It sits between two genes with no prior association with multiple sclerosis, called DYSF and ZNF638: the former is involved in repairing damaged cells, the latter helps control viral infections. The proximity of the variant to these genes suggests that they may be involved in disease progression. To confirm their findings, the scientists then studied the genetics of nearly 10,000 other MS patients, noting that those with two copies of the variant develop disabilities faster.
The DYSF and ZNF638 genes “are normally active in the brain and spinal cord, and not in the immune system,” said Adil Harroud, first author of the study. Therefore “our findings suggest that resilience and repair in the nervous system determine the course of multiple sclerosis progression and that we should focus on these parts of human biology for more effective therapies.” For the expert, this research offers “a new opportunity to develop new drugs that can help preserve the health of all those who suffer from MS”.
The published data thus represent the first clues to addressing the nervous system component of MS. “Although it seems obvious that the brain’s resilience to injury would determine the severity of a disease like MS, this new study has pointed us towards the key processes that underlie this resilience,” Sawcer said. More work will be needed to determine exactly how the identified genetic variant affects the DYSF and ZNF638 genes, and the nervous system more generally. Scientists are also collecting an even larger set of DNA samples from people with MS, expecting to find other variants that contribute to long-term disability in the disease.
The study was supported in part by funding from the NIH’s National Institute on Neurological Disorders and Stroke (NINDS), the European Union’s Horizon 2020 program, and the Multiple Sclerosis Society of Canada. The Italian researchers involved have received funds that over the years have allowed them to contribute to this study from Fism (Italian Multiple Sclerosis Foundation) and the Ministry of Health.
In Italy, the research was coordinated by Sandra D’Alfonso, professor of medical genetics – Department of Health Sciences at the University of Eastern Piedmont in Novara (who together with Maurizio Leone of the Casa Sollievo della Sofferenza Foundation heads Progemus, a of Sm centers which participated in the study and which includes the neurological clinic of the Aou ‘Maggiore della Carità’ of Novara) and by Filippo Martinelli Boneschi, professor of Neurology – Department of Health Sciences of UniMi and head of the Multiple Sclerosis Center of the ‘Asst Santi Paolo and Carlo of Milan, both members of the strategic group of the Imsgc, as well as by Federica Esposito, head of the Laboratory of Human Genetics of Neurological Diseases of the San Raffaele of Milan and member of the Imsgc with Massimo Filippi, head of the Unit of Neurology, Neurorehabilitation and Neurophysiology and the San Raffaele Sm Center in Milan.
The Italian scientists – highlights the State University of Milan – actively contributed to all the steps of the work, from the original design to the analysis and preparation phases of the article. They also made available a large national case series of people with multiple sclerosis accurately characterized from a clinical point of view, equal to about 20% of the total patients examined, providing data relating to a large component of a population in southern Europe, otherwise not represented in the overall series. “This work – declare D’Alfonso, Martinelli Boneschi and Esposito – represents an important turning point in the field of precision medicine, as it could, for example, lead to the use of more aggressive therapies right from the start in those subjects with variants unfavorable genetics for progression. Furthermore, the knowledge of this variant and of the two genes close to the variant could allow the development of new drugs that act on the mechanism of action of these two genes and slow down the progression of the disease”.
Other Italian collaborators are Nadia Barizzone, Department of Health Sciences – University of Eastern Piedmont Novara; Paola Cavalla, Department of Neuroscience and Mental Health – Aou Citta della Salute e della Scienza of Turin; Ferdinando Clarelli, Elisabetta Mascia, Silvia Santoro and Melissa Sorosina of the Irccs San Raffaele hospital in Milan; Domenico Caputo of the Irccs Don Gnocchi Foundation Onlus in Milan; Giancarlo Comi, Honorary Vita-Salute San Raffaele University of Milan; Domizia Vecchio, Neurological Clinic Aou Maggiore della Carità, Novara.
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