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

Overview

Journal Biomolecules

Publisher MDPI

Specialties Biochemistry
Molecular Biology

Date 2022 Oct 27

PMID 36291640

Authors

Francesco Errico

Carmen Marino

Manuela Grimaldi

Tommaso Nuzzo

Valentina Bassareo

Valeria Valsecchi

Chiara Panicucci

Elia Di Schiavi

Tommaso Mazza

Claudio Bruno

Adele DAmico

Manolo Carta

Anna Maria DUrsi

Enrico Bertini

Livio Pellizzoni

Alessandro Usiello

Affiliations

Soon will be listed here.

Abstract

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.

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