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

Lars Hendrik Müschen,Susanne Petri,Olivia Schreiber-Katz,Flavia Wiehler,Omar Abu-Fares,Camilla Binz,Nora Möhn,Thomas Skripuletz,Gresa Ranxha,Paul Bronzlik,Friedrich Götz,Martin W Hümmert,Alma Osmanovic,Stefan Gingele,Konstantin F Jendretzky,Martin Stangel

doi:10.3390/brainsci11030296

Lars Hendrik Müschen, Susanne Petri + Show 14 more

Open Access

https://doi.org/10.3390/brainsci11030296

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Journal: Brain sciences	Publication Date: Feb 26, 2021
Citations: 13	License type: CC BY 4.0

Affiliation: Hannover Medical School

Abstract

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.

Highlights

Licensee MDPI, Basel, Switzerland.With U.S Food and Drug Administration (FDA) approval of the antisense oligonucleotide (ASO) nusinersen, the first disease-modifying treatment for 5q-spinal muscular atrophy (SMA) has become available [1]
There was no significant difference between the cerebrospinal fluid (CSF) leukocyte count, CSF total protein levels, and QAlbumin values in patients who underwent computed tomography (CT)-guided lumbar puncture
Overviewing a treatment period of a maximum of 18 months, we observed a significant elevation in CSF total protein levels and respective QAlbumin values in 38.9% of cases during the first 10 months of treatment, mainly without significant changes in lactate levels, leukocyte count, and oligoclonal bands (OCB) status, which is consistent with previously published data [11]

Summary

Introduction

With U.S Food and Drug Administration (FDA) approval of the antisense oligonucleotide (ASO) nusinersen, the first disease-modifying treatment for 5q-spinal muscular atrophy (SMA) has become available [1]. The almost identical SMN2 gene, which is commonly present in several copies, differs only in a single nucleotide. This change causes the disruption of an exonic splice enhancer in exon 7, and the gene encodes only low levels of the functional SMN protein [4]. ASO-based therapies in SMA modify splicing of SMN2 at the pre-mRNA level and thereby increase the production of the functional, full-length SMN protein [6]. Nusinersen has been shown to effectively target the central nervous system and substantially prolong survival and improve motor function in SMA patients [7,8]

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