Cerebrospinal Fluid Parameters in Antisense Oligonucleotide-Treated Adult 5q-Spinal Muscular Atrophy Patients.

Approval of nusinersen, an intrathecally administered antisense oligonucleotide, for the treatment of 5q-spinal muscular atrophy (SMA) marked the beginning of a new therapeutic era in neurological diseases. Changes in routine cerebrospinal fluid (CSF) parameters under nusinersen have only recently been described in adult SMA patients. We aimed to explore these findings in a real-world setting and to identify clinical and procedure-associated features that might impact CSF parameters. Routinely collected CSF parameters (leukocyte count, lactate, total protein, CSF/serum albumin quotient (QAlbumin), oligoclonal bands) of 28 adult SMA patients were examined for up to 22 months of nusinersen treatment. Total protein and QAlbumin values significantly increased in the first 10 months, independent of the administration procedure. By month 14, no further increases were detected. Two patients developed transient pleocytosis. In two cases, positive oligoclonal bands were found in the beginning and in four patients throughout the whole observation period. No clinical signs of inflammatory central nervous system disease were apparent. Our data confirm elevated CSF total protein and QAlbumin during nusinersen treatment. These alterations may be caused by both repeated lumbar punctures and the interval between procedures rather than by the medication itself. Generally, there were no severe alterations of CSF routine parameters. These results further underline the safety of nusinersen therapy.

Treatment expectations and patient-reported outcomes of nusinersen therapy in adult spinal muscular atrophy.

BACKGROUND: The antisense-oligonucleotide (ASO) nusinersen has recently been approved as the first genetically modifying therapy for 5q-associated spinal muscular atrophy (SMA) based on randomized sham-controlled trials in infants and children. The efficacy in adults with long disease history and advanced disease status is still widely unknown; the same applies to specific expectations of adult SMA patients and to what extent they are met and may impact outcome measures. METHODS: In a longitudinal monocentric study in adult patients with SMA types 2-4, the Stanford Expectations of Treatment Scale (SETS) was assessed prior to and during nusinersen treatment. Treatment outcome was evaluated using patient-reported outcomes (PROs) as well as objectively quantifiable motor outcome measures. RESULTS: Adult SMA patients had high expectations of nusinersen treatment effectiveness regarding increase in muscle strength and disease stabilization. Via PROs, 75% stated improvements in muscle strength, endurance and independence under therapy which was in line with slight improvements in quantifiable motor scores during a  ten month observation period. In contrast, patients only expressed few negative expectations which further decreased during therapy. CONCLUSIONS: This study showed mainly positive treatment expectations and PROs in patients undergoing nusinersen treatment along with measurable functional improvement in adult SMA patients. Moreover, treatment expectations did not significantly influence outcome measures.

Chemokine CXCL13 as a New Systemic Biomarker for B-Cell Involvement in Acute T Cell-Mediated Kidney Allograft Rejection.

The presence of B-cell clusters in allogenic T cell-mediated rejection (TCMR) of kidney allografts is linked to more severe disease entities. In this study we characterized B-cell infiltrates in patients with TCMR and examined the role of serum CXCL-13 in these patients and experimentally. CXCL-13 serum levels were analyzed in 73 kidney allograft recipients at the time of allograft biopsy. In addition, four patients were evaluated for CXCL13 levels during the first week after transplantation. ELISA was done to measure CXCL-13 serum levels. For further mechanistic understanding, a translational allogenic kidney transplant (ktx) mouse model for TCMR was studied in BalbC recipients of fully mismatched transplants with C57BL/6 donor kidneys. CXCL-13 serum levels were measured longitudinally, CD20 and CD3 composition and CXCL13 mRNA in tissue were examined by flow cytometry and kidneys were examined by histology and immunohistochemistry. We found significantly higher serum levels of the B-cell chemoattractant CXCL13 in patients with TCMR compared to controls and patients with borderline TCMR. Moreover, in patients with acute rejection within the first week after ktx, a >5-fold CXCL13 increase was measured and correlated with B-cell infiltrates in the biopsies. In line with the clinical findings, TCMR in mice correlated with increased systemic serum-CXCL13 levels. Moreover, renal allografts had significantly higher CXCL13 mRNA expression than isogenic controls and showed interstitial CD20+ B-cell clusters and CD3+ cell infiltrates accumulating in the vicinity of renal vessels. CXCL13 blood levels correlate with B-cell involvement in TCMR and might help to identify patients at risk of a more severe clinical course of rejection.