Biomarkers for Adult SMA Patients Treated With Nusinersen Remain Elusive

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As spinal muscular atrophy (SMA) treatments advance, new biomarkers that correlate with clinical outcomes are needed to gauge treatment response.

Identifying biomarkers for spinal muscular atrophy (SMA) has become a priority as disease-modifying therapies like nusinersen arise in the treatment landscape, but research has not yet delivered consistent, robust results in this area. A study published in Clinical Drug Investigation aimed to find potential biomarkers for nusinersen treatment response in cerebrospinal fluid (CSF) and serum samples that correlate with motor function status in SMA.

SMA is a genetic neurodegenerative disease caused by homozygous deletion or point mutation in the SMN1 gene, which produced SMN protein. While SMN2 gene copies can produce some SMN, it is not enough to compensate for the lack of functioning SMN1. SMA has a range of phenotypes between type 0 (the most severe, which is characterized by prenatal onset and death early after birth) to type 4 (adult onset with mild motor function symptoms and slow progression).

The single-center cohort study included SMA patients 18 years of age or older who were treated with nusinersen intrathecally from October 2018 to January 2021. Eligibility requirements included falling into the SMA type 2 (SMA2) or SMA type 3 (SMA3) phenotypes. The authors noted that although some studies have pointed to potential prognostic CSF biomarkers in SMA type 1, there is less significant data on late-onset SMA.

The SMA cohort included 9 patients (3 with SMA2, 6 with SMA3) meeting the study requirements, and a control cohort included 12 patients who had no neurological diseases and were matched for age and sex with the SMA group.

In evaluations pre-administration (T0) and at each maintenance dose (T2-T5), patients were defined as walkers, sitters, or non-sitters — common descriptors of SMA phenotype/severity. The Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module for SMA (RULM) were used to gauge clinical severity during each assessment. The 6-minute walking test (6MWT) was a clinical outcome in patients who could walk.


CSF and serum samples were collected and immediately analyzed, which included measures of:

  • CSF cells count
  • CSF/serum glucose ratio
  • CSF/serum albumin ratio (Qalb), with normal values defined as less than 6.5 for patients aged 18-40 years, less than 8.0 for patients aged 41-60 years, and less than 9.0 for patients over 60 years of age
  • IgG oligoclonal bands (OCBs) in CSF or serum
  • Neurofilaments (NFL)
  • Tau and phosphor-Tau (p-Tau)
  • Creatinine levels in serum

Clinically, there were increases in both RULM and HFMSE between T0 and each other time point, but there were no improvements found between sequential time points (T1-T5). The 6MWT saw a similar trend in the 2 patients who could walk, increasing between T0 and T1 but remaining stable thereafter during 18 months of follow-up. This finding does not align with previous studies, which saw further improvement throughout treatment. The authors hypothesize that the small and phenotypically heterogeneous cohort could have affected the power of their statistical analysis in this regard.

The motor scales could also underestimate improvements in patients who are weaker or stronger at baseline.

“New outcome measures should probably be developed and/or validated in a larger cohort of adult SMA patients or at least different motor scales should be used after stratifying patients according to the functional subgroups (non-sitters, sitters, walkers),” they wrote.

CSF and Serum Markers

In contrast to studies of pediatric SMA patients, there was no evidence of any specific and sensitive CSF biomarkers of nusinersen efficacy or biomarkers correlating with motor function in this small study. NFL, Tau and p-Tau levels in CSF were similar to age-matched controls, consistent with other studies of these SMA subgroups. Serum creatinine levels were lower in SMA patients compared with the control cohort, and as other studies have found, they correlated with disease duration and motor function. So while they did not change during nusinersen treatment, creatinine levels can be a biomarker of disease severity.

There were some findings that the authors consider noteworthy, despite the lack of specific and sensitive biomarkers.

At baseline and during treatment, there were abnormalities in the serum and CSF parameters that the study focused on. As far as Qalb, blood-brain barrier damage was detected in 3 SMA patients at baseline, and Qalb increased slightly but significantly in 7 of 9 patients after the loading dose of nusinersen. The baseline levels may be explained by CSF flow dysfunction due to spinal stenosis or scoliosis, a common characteristic of SMA. Repeated lumbar punctures may explain the significant increases, the authors noted. “We agree with previous studies that suggested routinely monitoring albumin CSF/serum ratio as a security marker of CSF flow dysfunction at each administration of nusinersen.”

At baseline, 5 patients had systemic OCBs present and 1 had associated intrathecal OCBs, suggesting an immunological involvement. They characterizes the finding as non-specific and ambiguous, but wrote, “To explain the action of immune system in SMA, the future direction should be to characterize the IgG OCBs bands during nusinersen treatment, to investigate other markers of systemic immune activation, and to identify the possible development of anti-drug antibodies that could influence the efficacy of nusinersen.”

“Our study suggested that the development of blood-brain barrier dysfunction and both systemic and intrathecal OCBs in some SMA patients could be due to repeated lumbar puncture and the immunogenic effect of nusinersen,” the authors concluded. ‘Furthermore, biomarkers of neurodegeneration did not play a prognostic role in our cohort of adult SMA patients.


Milella G, Introna A, D’Errico E, et al. Cerebrospinal fluid and clinical profiles in adult type 2–3 spinal muscular atrophy patients treated with nusinersen: An 18-month single-centre experience. Clin Drug Investig. Published online August 13, 2021. doi:10.1007/s40261-021-01071-0