Targeted antisense oligonucleotide treatment rescues developmental alterations in spinal muscular atrophy organoids
Year: 2025
Type: article
Abstract: Spinal muscular atrophy (SMA) is a severe neurological disease caused by mutations in the SMN1 gene, characterized by early onset and degeneration of lower motor neurons. Understanding early neurodevelopmental defects in SMA is crucial for optimizing therapeutic interventions. Using spinal cord and cerebral organoids generated from multiple SMA type 1 male donors, we revealed widespread disease mechanisms beyond motor neuron degeneration. Single-cell transcriptomics uncovered pervasive alterations across neural populations, from progenitors to neurons, demonstrating SMN-dependent dysregulation of neuronal differentiation programs. Multi-electrode array (MEA) analysis identified consistent hyperexcitability in both spinal and brain organoids, establishing altered electrical properties as a central nervous system-wide feature of pathogenesis. Early administration of an optimized antisense oligonucleotide (ASO) that increased SMN levels rescued morphological and functional deficits in spinal cord organoids across different genetic backgrounds. Importantly, this early intervention precisely corrected aberrant splicing in here identified SMN1 targets enriched at critical nodes of neuronal differentiation. Our findings demonstrate that early developmental defects are core features of SMA pathogenesis that can be prevented by timely therapeutic intervention, providing insights for optimizing treatment strategies.
Source: Nature Communications
Authors: Irene Faravelli, Paola Rinchetti, Monica Tambalo, Illia Simutin, Lisa Mapelli, Sara Mancinelli, Matteo Miotto, Mafalda Rizzuti, Andrea D’Angelo, Chiara Cordiglieri, Giulia Forotti, Clelia Peano, Paolo Kunderfranco, Luca Calandriello, Giacomo P. Comi, Elvezia Paraboschi, Eleonora Pali, Francesca Beatrice, Egidio D’Angelo, Serge Przedborski, Monica Nizzardo, Simona Lodato, Stefania Corti
Institutions: Harvard University, University of Milan, Columbia University, Humanitas University, University of Pavia, IRCCS Humanitas Research Hospital, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Istituto Nazionale Genetica Molecolare, Human Technopole, Institute of Genetic and Biomedical Research, National Research Council, Fondazione Istituto Neurologico Nazionale Casimiro Mondino
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,990
OpenAlex ID: W4417530669