Cerebrospinal fluid characteristics of patients treated with intrathecal nusinersen for spinal muscular atrophy

Abstract

Introduction/Aims There is limited information on the potential effects of repeated intrathecal antisense oligonucleotide drug delivery on cerebrospinal fluid (CSF) biochemical and blood cell profiles. This study aimed to examine longitudinal changes in the biochemical components (glucose, protein) and blood cell counts in the CSF of spinal muscular atrophy (SMA) patients treated with intrathecal nusinersen. Methods We collected and analyzed clinical and CSF parameters (cell count, protein, glucose, culture) of 50 individuals with SMA during nusinersen treatment (22 type 1, 17 type 2, and 11 type 3). Results The median protein concentration at baseline and during treatment was within the normal range but rose during treatment and was significantly above baseline at the time of the ninth intrathecal injection (p = 0.02, two‐tailed Wilcoxon matched‐pairs test, and p = 0.0015, Friedman test for repeated measures). Further analysis showed that the increase in CSF protein concentration was evident for SMA types 2 and 3 patients, but not for type 1. This observation was also demonstrated by a significant correlation between the SMN2 gene copy number and the increase in CSF protein concentration (Spearman rank correlation test). Discussion Our results demonstrate that a delayed increase in CSF protein concentration is expected during nusinersen treatment for SMA types 2 and 3. This might reflect the medication's effect and a possible therapeutic biochemical marker.

The impact of three SMN2 gene copies on clinical characteristics and effect of disease-modifying treatment in patients with spinal muscular atrophy: a systematic literature review

“…Overall, 23 studies on SMA treatment included SMN2 copy number ( 67–89 ), but only 11 of these studies examined treatment effects in patients with three SMN2 copies ( Supplementary Table S6 ) ( 68 , 69 , 71 , 74 , 79 , 80 , 83 , 85 , 87–89 ). The 12 excluded studies did not allow analysis of treatment effects in patients with three SMN2 copies ( Supplementary Table S7 ) ( 67 , 70 , 71 , 73 , 75–78 , 81 , 82 , 84 , 86 ).…”

Symptomatic intracranial hypertension in an adult patient with spinal muscular atrophy and arachnoid cysts receiving nusinersen

“…Studies looking at routine CSF parameters of patients with SMA receiving nusinersen have consistently shown a mild increase in CSF protein and CSF/serum quotients of albumin without further signs of inflammation. This has been discussed to be the result of either nusinersen treatment or repeated lumbar punctures [11][12][13]. In rats, using multimodal imaging and radioactively and fluorescently labelled ASO, it was shown that after intrathecal injection they strongly associate with the meninges and are subsequently transported to lymph nodes [14].…”

Identifying Biomarkers of Spinal Muscular Atrophy for Further Development

“…[ [180][181][182] tion factors [95][96][97][98][99], and long non-coding RNAs [100][101][102][103]; biomolecular factors such as SMN protein [18,39,48,57,81,[104][105][106], neurofilament (NF) [78,[107][108][109][110][111][112][113][114][115][116][117][118], tau protein [112,[119][120][121], and muscle damage indicators [122][123][124]; muscle imaging parameters including magnetic resonance imaging (MRI) [122][123][124] and electrical impedance myography (EIM) [75,[125][126][127]; and electrophysiological parameters including compound muscle action potential (CMAP) [128]…”