Spinal Muscular Atrophy Begins Before Birth: A Study Reveals Its Origin

An Italian study conducted on organoids reveals early defects in the development of the central nervous system already in the embryonic phase, reinforces the crucial importance of neonatal screening, and opens new therapeutic perspectives.

Spinal Muscular Atrophy or SMA – a disease of the nervous system traditionally associated with motoneuron neurodegeneration – affects the central nervous system much earlier than previously thought, already in the very early stages of embryonic development. This is the central discovery of a study recently published in Nature Communications, resulting from a collaboration that brought together research groups from the “Centro Dino Ferrari“, the University of Milan, Humanitas University, and the IRCCS Ca’ Granda Ospedale Maggiore Policlinico, with contributions from Columbia University in New York.

The research, coordinated by Stefania Corti, Professor of Neurology at the University of Milan and Director of the SSD Neuromuscular and Rare Diseases at the Policlinico di Milano, and Simona Lodato, Professor of Human Anatomy at Humanitas University and group leader of the Neuroscience Development Laboratory at the IRCCS Istituto Clinico Humanitas, overturns the traditional view of SMA as a disease exclusively of the motoneuron. By using organoids, three-dimensional structures derived from patient cells that miniaturize nervous tissue, the two researchers and their teams were able to observe what happens in the nervous system of patients from the very early stages of its development.

“We discovered that the deficiency of SMN, a fundamental protein for the functioning of motoneurons and whose lack is a direct cause of SMA, does not only damage mature motoneurons but profoundly alters differentiation programs already at the level of neural progenitors,” explains Stefania Corti. “This means that the disease begins much earlier than the onset of symptoms, reinforcing the crucial importance of neonatal screening and early treatment.”

“Organoids have opened a window to biological processes that were previously inaccessible,” adds Simona Lodato. “For the first time, we were able to follow in real-time how the lack of SMN compromises neuronal development trajectories, creating a sort of ‘block’ in the maturation of cells. These tools are valuable not only for understanding the mechanisms of the disease but also for testing new therapeutic strategies in a human context.”

Single-cell sequencing analyses of these complex three-dimensional structures that recapitulate important steps in neuronal differentiation and the formation of functional networks revealed widespread alterations affecting various neuronal populations, beyond the already central motoneurons, while electrophysiological recordings highlighted abnormal hyperexcitability in both spinal and brain organoids, demonstrating that dysfunctions extend to the entire central nervous system.

The study also demonstrated that early treatment (with antisense oligonucleotides optimized for biodistribution, capable of increasing SMN protein levels) can correct both early morphological and functional defects, restoring normal patterns of electrical activity and significantly reducing cell death, which leads to the neurodegeneration observed in young SMA patients. A result that provides a solid scientific basis for the importance of timely therapeutic intervention in patients.

Spinal Muscular Atrophy remains one of the leading genetic causes of infant mortality, but therapies approved in recent years have radically changed the prognosis for patients. This study adds a fundamental piece to the understanding of the mechanisms underlying the disease, indicating that the greatest benefits are obtained when treatment begins before damage to the nervous system becomes irreversible, ideally in the presymptomatic phase, also thanks to neonatal screening.

The publication represents the culmination of years of joint work between institutions that constitute the excellence of Italian neurology and neuroscience. The “Centro Dino Ferrari” at the University of Milan and the Policlinico di Milano has been an international reference point for neuromuscular diseases for decades; the University of Milan has significantly contributed to the development of innovative disease models, including the organoids used in this study, and to the definition of new therapeutic approaches for SMA; Humanitas University and the IRCCS Istituto Clinico Humanitas have developed recognized expertise in the biology of the developing nervous system and the impact this can have on neurodegenerative diseases; the IRCCS Ca’ Granda Ospedale Maggiore Policlinico Foundation ensures that continuum between research and clinic that allows translating scientific discoveries into concrete benefits for patients.