Full-Length SMN Transcript in Extracellular Vesicles as Biomarker in Individuals with Spinal Muscular Atrophy Type 2 Treated with Nusinersen

Abstract

Background: Three therapeutic strategies have radically changed the therapeutic scenario for spinal muscular atrophy (SMA). However, therapeutic response differs between individuals. There is a need to identify biomarkers to further assess therapeutic response and to better understand which variables determine the extent of response. Methods: We conducted a study using an optimized digital droplet PCR-based method for the ultra-sensitive detection of SMN transcript in serum EVs from SMA 2 individuals treated with nusinersen over 14 months. In parallel, we investigated levels of serum and CSF neurofilament heavy chain (pNF-H) in the same cohort. Results: Expression of flSMN transcript in EVs of SMA 2 individuals prior to nusinersen was lower than in controls (0.40 vs 2.79 copies/ul; p < 0.05) and increased after 14 months of nusinersen (0.40 vs 1.11 copies/ul; p < 0.05). The increase in flSMN with nusinersen was significantly higher in younger individuals (p < 0.05). Serum pNF-h was higher in non-treated individuals with SMA 2 than in controls (230.72 vs 22.88 pg/ml; p < 0.05) and decreased with nusinersen (45.72 pg/ml at 6 months, 39.02 pg/ml at 14 months). CSF pNF-h in SMA 2 individuals also decreased with nusinersen (248.04 pg/ml prior to treatment, 197.10 pg/dl at 2 months, 104.43 pg/dl at 6 months, 131.03 pg/dl at 14 months). Conclusions: We identified an increase decline of flSMN transcript in serum EVs of SMA 2 individuals treated with nusinersen that was more pronounced in the younger individuals. Our results indicate that flSMN transcript expression in serum EVs is a possible biomarker in SMA to predict or monitor the response to treatment.

Role of circulating biomarkers in spinal muscular atrophy: insights from a new treatment era

“…Idem, in a study involving patients treated with nusinersen, an increase in SMN-FL levels in extracellular vesicles blood was observed after 14 months of treatment (60). In the first-in-human study with risdiplam, it was shown that FL SMN2 mRNA levels and SMN protein levels increase in whole blood after treatment (56,57).…”

“…The Biomarkers for SMA (BforSMA) study is an example of this effort. It was a cross-sectional omics study that evaluated blood and urine protein analytes in children (age 2-12 years) with genetically confirmed SMA and age-matched healthy controls (60). A resulting 200 candidate biomarkers were found to correlate with motor scores, and the most significant markers across all outcome measures were plasma protein analytes.…”

Molecular Biomarkers for the Diagnosis, Prognosis, and Pharmacodynamics of Spinal Muscular Atrophy

“…Table 2 demonstrates that NfL and pNfH were used as potential pharmacodynamic (response) biomarkers in the majority of studies that examined the utility of molecular biomarkers for monitoring therapeutic response in SMA. In the majority of studies, a decrease in NfL and pNfH levels was observed following treatment with nusinersen [39,[61][62][63][76][77][78][79][80][81], whereas others observed no change in the levels of these biomarkers [45,56,60,[82][83][84] (Table 2).…”