Nusinersen Modulates Proteomics Profiles of Cerebrospinal Fluid in Spinal Muscular Atrophy Type 1 Patients.

Laura Bianchi,Francesca Polito,Luca Bini,Fabrizio Di Giuseppe,Sonia Messina,Lorenza Vantaggiato,Antonio Versaci,Eloisa Gitto,Stefania Angelucci,M’Hammed Aguennouz,Maria Sframeli,Rosaria Oteri,Annamaria Ciranni,Gian Luca Vita,Giuseppe Vita

doi:10.3390/ijms22094329

Abstract

Spinal muscular atrophy (SMA) type 1 is a severe infantile autosomal-recessive neuromuscular disorder caused by a survival motor neuron 1 gene (SMN1) mutation and characterized by progressive muscle weakness. Without supportive care, SMA type 1 is rapidly fatal. The antisense oligonucleotide nusinersen has recently improved the natural course of this disease. Here, we investigated, with a functional proteomic approach, cerebrospinal fluid (CSF) protein profiles from SMA type 1 patients who underwent nusinersen administration to clarify the biochemical response to the treatment and to monitor disease progression based on therapy. Six months after starting treatment (12 mg/5 mL × four doses of loading regimen administered at days 0, 14, 28, and 63), we observed a generalized reversion trend of the CSF protein pattern from our patient cohort to that of control donors. Notably, a marked up-regulation of apolipoprotein A1 and apolipoprotein E and a consistent variation in transthyretin proteoform occurrence were detected. Since these multifunctional proteins are critically active in biomolecular processes aberrant in SMA, i.e., synaptogenesis and neurite growth, neuronal survival and plasticity, inflammation, and oxidative stress control, their nusinersen induced modulation may support SMN improved-expression effects. Hence, these lipoproteins and transthyretin could represent valuable biomarkers to assess patient responsiveness and disease progression.

Highlights

IntroductionSpinal muscular atrophy (SMA) is an autosomal recessive disease affecting approximately one in 10,000 live births and having a carrier frequency of about one in 50 [1,2]
The spontaneous course of Spinal muscular atrophy (SMA) type 1 does not expect any clinical improvement over time, as this is a progressive disease characterized by a rapid degeneration of motor neurons
Our analyses have evidenced nusinersen modulating cerebrospinal fluid (CSF) protein-pattern in the pediatric SMA-patients we enrolled. As all they were alive, none showed adverse events, but on the contrary, they presented a significant improvement in motor functions, the protein differences we identified occurring between CSF at baseline and after the treatment may be correlated to the disease amelioration

Summary

Introduction

Spinal muscular atrophy (SMA) is an autosomal recessive disease affecting approximately one in 10,000 live births and having a carrier frequency of about one in 50 [1,2]. SMA type 1, which constitutes around 60% of SMA cases [1,2], presents symptom onset before the age of six months and it is commonly characterized by severe hypotonia, symmetrical muscle weakness, and respiratory and feeding difficulties. Untreated SMA type 1 patients never acquire the ability to sit, and they usually die within the age of two years because of respiratory failure.

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