Objective: To evaluate the effect of nusinersen on CSF markers of neuroaxonal damage and astrocyte activation and motor outcomes in adult patients with SMA.

Background: The efficacy of nusinersen in SMA adult patients is largely unknown and assessment of clinical outcomes is complicated by symptom burden and slow functional decline. 

Methods: We studied 17 adults with SMA (6 Type 2, 11 Type 3, median age at first dose 36.3 years, range 18.26-63.8). NfL and GFAP concentrations were measured prior to each administration of nusinersen over a median of 14.33 months (range 5.75 – 19.10). Revised Upper Limb Module (RULM) scores pre- and post-treatment initiation were available for 4 Type 2 and 10 Type 3 participants. The changes in molecule concentrations and motor score over time were examined using mixed effect models. 

Results: There was a positive correlation between age and CSF NfL (p=0.017) and GFAP (p<0.0001). Upon treatment, NfL showed a progressive decrease (-1.02 pg/mL/month, p=0.0011), with greater decrease in Type 2 than Type 3 (-1.05 pg/mL/month, p=0.0016). GFAP decreased only for Type 3 patients (-1.01 pg/mL/month, 0.0085). Type 2 patients showed no significant GFAP change (1.00 pg/mL/month p = 0.73). The pre-treatment RULM scores showed a non-significant inverse association with the pre-treatment levels of NfL (right arm p=0.15) and GFAP (right arm p=0.10). Following treatment, Type 3 patients demonstrated an increase in motor performance in both hands (left hand p=0.0047, right hand p=0.0015). All Type 2 patients scored a persistent “0” on the RULM except for one, who showed increased RULM score over 13 months (Right: 2 to 5, Left: 1 to 5). 

Conclusions: Nusinersen appeared to improve motor performance in Type 3 patients. The effect on biomarkers was mixed based upon SMA type. Biomarker measures may be complicated by variations based on age and our small sample size.