Multiomics profiling in Spinal Muscular Atrophy (SMA): Insights from longitudinal CSF analysis of patients under treatment with Nusinersen

Spinal Muscular Atrophy (SMA) is a rare neuromuscular disease caused by biallelic mutations in the SMN1 gene, leading to progressive muscle weakness due to degeneration of the anterior horn cells. Since 2017, SMA patients can be treated with the anti-sense oligonucleotide Nusinersen, which promotes alternative splicing of the SMN2 gene, by regular intrathecal injections. In this prospective study we applied metabol-, lipid-, and proteomic analysis to examine sequential CSF samples from 13 SMA patients and controls. This multiomic approach identified over 800 proteins and 400 small molecules including lipids. Multivariate analysis of multiomic data successfully discriminated between the CSF derived from SMA patients and control subjects. Lipidomic analysis revealed increased levels of cholesteryl esters and lyso-phospholipids, along with reduced levels of cholesterol and phospholipids in the CSF of SMA patients as compared to the healthy control group. This data, combined with results from functional assays, led us to conclude that SMA patients exhibit altered levels and function of HDL-like particles in the CSF. Notably, Nusinersen therapy was observed to reverse disease-specific profile changes towards a physiological state, potentially explicable by restoring HDL-function.