Longitudinal Proteomic Fingerprinting in CSF of Nusinersen-Treated Patients with 5q-Associated Spinal Muscular Atrophy

ABSTRACT: Abstract Introduction: 5q-associated spinal muscular atrophy (SMA) is a motor neuron disease causing progressive alpha motor neuron degeneration, muscle atrophy, and weakness. Intrathecal therapy with the antisense oligonucleotide Nusinersen modifies the disease course. However, biomarkers for understanding underlying molecular pathomechanisms and monitoring therapy are not yet known. Methods: 130 cerebrospinal fluid (CSF) samples from 24 SMA type 2 and 3 adult patients were collected over 3.5 years and CSF proteome was using mass spectrometry (MS). By employing two complementary MS protein quantification methods, label-free quantification (LFQ) and tandem mass tag (TMT) isotopic labeling, specific protein patterns reflecting changes in the CSF in the context of nusinersen therapy were identified. These results were combined with cellular and metabolic profiles. Results: Nusinersen therapy led to a median motor function improvement of 2.2 Hammersmith Functional Motor Scale Expanded points after 10 months and 2.6 points after 34 months. Albumin concentration and albumin quotient (CSF/serum) increased, as did the number of macrophages in the CSF under nusinersen therapy. Albumin, glucose, and lactate concentrations were inversely correlated with clinical improvement. MS analysis of CSF identified 1,674 (TMT) and 441 (LFQ) proteins. Protein profiles associated with clinical improvement reflected the reconstitution of neuronal circuits. Additionally, clinical improvement was associated with reduced humoral mediators of the immune response such as complement factors and immunoglobulins and cellular mediators such as lymphocytes. Discussion: Our multi-proteomic analysis provides new insights into the pathobiology of SMA and defines potential biomarker profiles in CSF for the disease course under nusinersen therapy.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cerebrospinal Fluid

DISEASE(S): Spinal Muscular Atrophy

SUBMITTER: Uwe Warnken  

LAB HEAD: Prof. Dr. med. Wolfgang Wick

PROVIDER: PXD054900 | Pride | 2025-05-07

REPOSITORIES: Pride