CNR ExploRA

Articolo in rivista, 2022, ENG, 10.3390/biom12101431

Nusinersen Induces Disease-Severity-Specific Neurometabolic Effects in Spinal Muscular Atrophy

Errico, Francesco; Marino, Carmen; Grimaldi, Manuela; Nuzzo, Tommaso; Bassareo, Valentina; Valsecchi, Valeria; Panicucci, Chiara; Di Schiavi, Elia; Mazza, Tommaso; Bruno, Claudio; D'Amico, Adele; Carta, Manolo; D'Ursi, Anna Maria; Bertini, Enrico; Pellizzoni, Livio; Usiello, Alessandro

CEINGE-Biotecnologie Avanzate S.c.a r.l.; IRCCS Casa Sollievo della Sofferenza; Università degli Studi di Cagliari; Columbia University; Università degli Studi della Campania Luigi Vanvitelli; Università degli Studi di Genova; Consiglio Nazionale delle Ricerche; IRCCS Ospedale Pediatrico Bambino Gesù; Università degli Studi di Napoli Federico II; Istituto Giannina Gaslini; Università degli Studi di Napoli Federico II, Facoltà di Medicina e Chirurgia; Università degli Studi di Salerno

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.

Biomolecules 12 (10)