Nusinersen Induces Disease-Severity-Specific Neurometabolic Effects in Spinal Muscular Atrophy
Francesco Errico,
Carmen Marino,
Manuela Grimaldi,
Tommaso Nuzzo,
Valentina Bassareo,
Valeria Valsecchi,
Chiara Panicucci,
Elia Di Schiavi,
Tommaso Mazza,
Claudio Bruno,
Adele D’Amico,
Manolo Carta,
Anna Maria D’Ursi,
Enrico Bertini,
Livio Pellizzoni,
Alessandro Usiello
Affiliations
Francesco Errico
Laboratory of Translational Neuroscience, Ceinge Biotecnologie Avanzate, 80145 Naples, Italy
Carmen Marino
Department of Pharmacy, University of Salerno, 84084 Fisciano, Italy
Manuela Grimaldi
Department of Pharmacy, University of Salerno, 84084 Fisciano, Italy
Tommaso Nuzzo
Laboratory of Translational Neuroscience, Ceinge Biotecnologie Avanzate, 80145 Naples, Italy
Valentina Bassareo
Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy
Valeria Valsecchi
Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, University of Naples “Federico II”, 80131 Naples, Italy
Chiara Panicucci
Center of Translational and Experimental Myology, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy
Elia Di Schiavi
Institute of Biosciences and BioResources (IBBR), CNR, 80131 Naples, Italy
Tommaso Mazza
IRCCS Casa Sollievo della Sofferenza, Bioinformatics Unit, 71013 San Giovanni Rotondo, Italy
Claudio Bruno
Center of Translational and Experimental Myology, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy
Adele D’Amico
Unit of Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences, Bambino Gesù Children’s Hospital IRCCS, 00163 Roma, Italy
Manolo Carta
Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy
Anna Maria D’Ursi
Department of Pharmacy, University of Salerno, 84084 Fisciano, Italy
Enrico Bertini
Unit of Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences, Bambino Gesù Children’s Hospital IRCCS, 00163 Roma, Italy
Livio Pellizzoni
Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA
Alessandro Usiello
Laboratory of Translational Neuroscience, Ceinge Biotecnologie Avanzate, 80145 Naples, Italy
Intrathecal delivery of Nusinersen–an antisense oligonucleotide that promotes survival motor neuron (SMN) protein induction–is an approved therapy for spinal muscular atrophy (SMA). Here, we employed nuclear magnetic resonance (NMR) spectroscopy to longitudinally characterize the unknown metabolic effects of Nusinersen in the cerebrospinal fluid (CSF) of SMA patients across disease severity. Modulation of amino acid metabolism is a common denominator of biochemical changes induced by Nusinersen, with distinct downstream metabolic effects according to disease severity. In severe SMA1 patients, Nusinersen stimulates energy-related glucose metabolism. In intermediate SMA2 patients, Nusinersen effects are also related to energy homeostasis but involve ketone body and fatty acid biosynthesis. In milder SMA3 patients, Nusinersen mainly modulates amino acid metabolism. Moreover, Nusinersen modifies the CSF metabolome of a more severe clinical group towards the profile of untreated SMA patients with milder disease. These findings reveal disease severity-specific neurometabolic signatures of Nusinersen treatment, suggesting a selective modulation of peripheral organ metabolism by this CNS-directed therapy in severe SMA patients.
