Nusinersen is the first approved drug for the treatment of spinal muscular atrophy (SMA). Treatment of SMA with nusinersen is based on a fixed dosing regimen. For other motoneuron diseases, such as amyotrophic lateral sclerosis (ALS), biomarkers are available for clinical diagnostics; however, no such biomarkers have yet been found for SMA. Serum and cerebrospinal fluid (CSF) samples of 11 patients with adult SMA type 3 were prospectively collected and analyzed during loading with nusinersen. Neurofilament heavy chain, tau protein, S100B protein, and neuron-specific enolase were investigated as potential biomarkers of motor neuron destruction. No significant pathological alterations in levels of neurofilament heavy chain, tau protein, or S100B protein were detected in the CSF or blood samples under baseline conditions or during loading with nusinersen. Neuron-specific enolase was marginally elevated in CSF and blood samples without significant alteration during treatment. In a mixed cohort of adult patients with SMA type 3, neurofilament heavy chain, tau protein, S100B protein, and neuron-specific enolase do not serve as potential biomarkers during the loading phase of nusinersen. The slow progression rate of SMA type 3 may not lead to detectable elevation of levels of these common markers of axonal degradation.

Background: Nusinersen is an intrathecally administered antisense oligonucleotide (ASO) that improves motor function in patients with spinal muscular atrophy (SMA). In addition to efficacy, the safety of a therapy is the decisive factor for the success of the treatment. For some ASOs, various organ toxicities have been described, such as thrombocytopenia, renal and liver impairment, or coagulation abnormalities. However, systematic data on laboratory parameters under treatment with nusinersen are mainly available from studies in infants and children. Therefore, our aim was to assess the safety of nusinersen therapy in adult SMA patients. Methods: Laboratory data from 404 nusinersen injections performed in 50 adult patients with SMA type 2 and type 3 were retrospectively analyzed. Results: The total observation period was 76.9 patient-years, and patients received up to 12 injections. Our data provides no new safety concerns. In cerebrospinal fluid (CSF), the mean white blood cell count and lactate remained stable over time. Total CSF protein increased by 2.9 mg/dL. No change in mean platelet count was observed under therapy. Only one patient showed sporadic mild thrombocytopenia. Coagulation parameters and inflammatory markers were stable. The mean creatinine level decreased by 0.09 mg/dL. Analysis of mean liver enzyme levels revealed no relevant changes during treatment. Conclusion: Our data demonstrate a favorable safety profile of nusinersen therapy in adult SMA patients under longer-term “real-world” conditions. In particular, we found no evidence of clinically relevant platelet declines, coagulopathies, or renal or hepatic organ toxicities, which are common concerns with the use of ASOs.

5q-Spinal muscular atrophy (SMA) is a severely disabling inherited neuromuscular disease that progressively reduces the motor abilities of affected individuals. The approval of the antisense oligonucleotide nusinersen, which has been shown to improve motor function in adult SMA patients, changed the treatment landscape. However, little is known about its impact on patients' quality of life (QoL), and there is still a need for adequate patient-reported outcome measures. In this study, we used the short form of the Neuro-QoL (Quality of Life in Neurological Disorders) for upper/lower extremity function to prospectively assess the health-related QoL of 17 adult SMA patients prior to initiation of nusinersen treatment and 2, 6, 10, and 14 months afterwards. At baseline, Neuro-QoL scores strongly correlated with motor function scores (Hammersmith Functional Motor Scale Expanded, HFMSE; Revised Upper Limb Module, RULM), but QoL did not increase significantly during the 14-month treatment period despite significant motor improvement as measured by HFMSE. Our results underline the need for novel, disease-specific assessments of QoL in SMA.

The antisense oligonucleotide nusinersen has been shown to improve trunk and limb motor function in patients with spinal muscular atrophy (SMA). Bulbar dysfunction, which is regularly present in SMA, is not captured by standard motor scores, and validated measurement instruments to assess it have not yet been established. Data on whether and how bulbar function changes under gene-based therapies in adult SMA patients are also unavailable. Here, we present data on the course of bulbar dysfunction assessed prospectively before nusinersen treatment initiation and 6 and 14 months later in 23 adult SMA patients using the Sydney Swallow Questionnaire (SSQ) and the bulbar subscore of the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R). While no improvement in bulbar scores was observed under treatment with nusinersen, the absence of a decline still implies a therapeutic effect of nusinersen on bulbar dysfunction. The results of this study aim to contribute to a standardized assessment of bulbar function in adult SMA patients, which may show therapeutic effects of gene-based therapies that are not evident from standard motor scores.

In previous studies, a below-average, average, or above-average intelligence quotient (IQ) in children with SMA was detected but, aside from a severe physical disability, the cognitive performance of adult SMA patients has not yet been evaluated. The intelligence test used in this study, the Wechsler Adult Intelligence Scale, fourth edition (WAIS-IV), was used to measure major intelligence components of adult SMA patients. The WAIS-IV determines four index scores representing verbal comprehension, perceptual reasoning, working memory, and processing speed. Due to time-dependent demands on motor function, the processing speed index score was excluded. IQ index scores of 33 adult SMA patients did not differ from IQ index scores of the normal population. In SMA type-3 patients, the index scores for verbal comprehension, perceptual reasoning, and working memory did not differ from the normal population but showed a trend of IQ scores towards lower points. Patients with SMA type 2 had lower IQ index scores for working memory (90.33 ± 12.95; p = 0.012) and perceptual reasoning (90.73 ± 12.58; p = 0.013) than the normal population. This study provided further evidence that SMA is a multi-systemic disease and may refute the widespread hypothesis that SMA patients might improve their cognitive skills to compensate for their physical impairment.