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Preliminary insights into RNA in CSF of SMA patients after Nusinersen “loading dose”

ABSTRACT: Antisense oligonucleotide (ASO) nusinersen (Spinraza®) modulates the pre–mRNA splicing of the SMN2 gene, allowing rebalance of biologically active SMN. It is administered intrathecally via lumbar puncture after removing an equal amount of cerebrospinal fluid (CSF). Its effect was proven beneficial and approved since 2017 for SMA treatment. Since the direct effect of nusinersen on RNA metabolism, the aim of this project was to evaluate cell-free RNA (cfRNA) in CSF of SMA patients under ASOs treatment for biomarker discovery.

ORGANISM(S): Homo sapiens

PROVIDER: GSE221900 | GEO | 2023/07/03

REPOSITORIES: GEO

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Type I PRMT inhibitor MS023 promotes SMN2 exon 7 inclusion and synergizes with nusinersen to rescue the phenotype of SMA mice

Project description:In our study we have identified MS023, an inhibitor of PRMTs, to increase SMN protein and FL SMN2 transcript levels, and to improve survival and weights of treated SMA mice, alone and in combination with currently approved antisense oligonucleotide. In order to understand the molecular underpinnings of the added benefit provided by the combinatorial treatment, we performed bulk transcriptomic analysis in spinal cords of SMA mice treated with MS023 only, nusinersen only, and MS023 in combination with nusinersen, compared to wild type and SMA littermates.

2023-03-01 | GSE206400 | GEO

Counteracting chromatin effects of a splicing-correcting antisense oligonucleotide improves its therapeutic efficacy in spinal muscular atrophy

Project description:Spinal Muscular Atrophy (SMA) is a motor-neuron disease caused by mutations of the SMN1 gene. The human paralog SMN2, whose exon 7 (E7) is predominantly skipped cannot compensate for the lack of SMN1. Nusinersen is an antisense oligonucleotide that upregulates E7 inclusion and SMN protein levels by displacing the splicing repressors hnRNPA1/A2 from their target site in intron 7. We show that, by promoting transcriptional elongation, the histone deacetylase inhibitor VPA cooperates with nusinersen to promote E7 inclusion. Surprisingly, nusinersen promotes the deployment of the silencing histone mark H3K9me2 on the SMN2 gene, creating a roadblock to PolII elongation that inhibits E7 inclusion. By removing the roadblock, VPA counteracts the undesired chromatin effects of nusinersen, resulting in higher E7 inclusion, without large pleiotropic effects, as assessed by genome-wide analyses. Combined administration of nusinersen and VPA in SMA mice strongly synergized in SMN expression, growth, survival, and neuromuscular function.

2022-06-09 | GSE167762 | GEO

Expression data from SMA fibroblasts treated with amiloride or EIPA

Project description:Spinal muscular atrophy (SMA) is an autosomal recessive, pediatric-onset disorder caused by the loss of spinal motor neurons thereby leading to generalized muscle atrophy. SMA is caused by the loss of or mutations in the survival motor neuron 1 (SMN1) gene. SMN1 is duplicated only in human to give rise to the paralogous SMN2 gene. These paralogs are nearly identical except for a cytosine to thymine (C-to-T) transition within an exonic splicing enhancer (ESE) element within exon 7. As a result, the majority of SMN2 transcripts lack exon 7 (SMNΔ7) which produces a truncated and unstable SMN protein. Since SMN2 copy number is inversely related to disease severity, it is a well-established target for SMA therapeutics development. 5-(N-ethyl-N-isopropyl)amiloride (EIPA), an inhibitor of sodium/proton exchangers (NHEs), has previously been shown to increase exon 7 inclusion and SMN protein levels in SMA cells. In this study several different types of NHE inhibitors were evaluated for their ability to modulate SMN2 expression. EIPA as well as 5-(N,N-hexamethylene)amiloride (HMA) increase exon 7 inclusion in SMN2 splicing reporter lines as well as in SMA fibroblasts. The EIPA-induced exon 7 inclusion occurs via a mechanism unique from that used by RG7800, another SMN2 splicing modulator, and does not involve previously identified splicing factors. Transcriptome analysis identified novel targets, including TIA1 and FABP3, for further characterization. EIPA and HMA are more selective at inhibiting the NHE5 isoform, which is expressed in fibroblasts as well as in neuronal cells. These results show that NHE5 inhibition increases SMN2 expression and may be a novel target for therapeutics development.

2022-06-16 | GSE179861 | GEO

Cell-mediated cytotoxicity surrounding the brain in spinal muscular atrophy

Project description:We here longitudinally investigated how SMA and nusinersen shaped local immune responses in the cerebrospinal fluid (CSF) using single cell RNA-sequencing and single cell TCR-sequencing.

2024-03-27 | GSE232391 | GEO

Cerebrospinal fluid proteomic profiling in nusinersen-treated patients with spinal muscular atrophy Cerebrospinal fluid proteomic profiling in nusinersen-treated patients with spinal muscular atrophy

Project description:Promising results from recent clinical trials on the approved antisense oligonucleotide nusinersen in pediatric patients with 5q-linked spinal muscular atrophy (SMA) still have to be confirmed in adult patients but are hindered by a lack of sensitive biomarkers that indicate an early therapeutic response. Changes of the overall neurochemical composition of cerebrospinal fluid (CSF) under therapy may yield additive diagnostic and predictive information. With this prospective proof-of-concept and feasibility study, we evaluated non-targeted CSF proteomic profiles by mass spectrometry along with basic CSF parameters of 10 adult patients with SMA types 2 or 3 before and after 10 months of nusinersen therapy, in comparison with 10 age- and sex-matched controls. These data were analyzed by bioinformatics and correlated with clinical outcomes assessed by the Hammersmith Functional Rating Scale Expanded (HFMSE). CSF proteomic profiles of SMA patients differed from controls. Two groups of SMA patients were identified based on unsupervised clustering. These groups differed in age and expression of proteins related to neurodegeneration and neuroregeneration. Intraindividual CSF differences in response to nusinersen treatment varied between patients who clinically improved and those who did not. Data are available via ProteomeXchange with identifier PDX015117. Comparative CSF proteomic analysis in adult SMA patients before and after treatment with nusinersen identified subgroups and treatment-related changes and may therefore be suitable for diagnostic and predictive analyses.

2020-01-07 | PXD016757 | Pride

Analysis of splicing changes in motoneurons from mice of a severe model for Spinal Muscular Atrophy (SMA)

Project description:Motoneuron cell bodies were isolated by laser capture microdissection from severe SMA mice at postnatal day 3. The comparison was between heterozygote carriers, SMA disease mice and SMA mice rescued by a U7 snRNA correcting the splicing of human SMN2.

2015-03-05 | E-MTAB-3170 | biostudies-arrayexpress

Cerebrospinal fluid proteomic profiling in nusinersen-treated patients with spinal muscular atrophy

Project description:Background: Promising results from recent clinical trials on the approved antisense oligonucleotide nusinersen in pediatric patients with 5q-linked spinal muscular atrophy (SMA) still have to be confirmed in adult patients but are hindered by a lack of sensitive biomarkers that indicate an early therapeutic response. Changes of the overall neurochemical composition of cerebrospinal fluid (CSF) under therapy may yield additive diagnostic and predictive information. Methods: In this prospective proof-of-concept and feasibility study, we evaluated non-targeted CSF proteomic profiles by mass spectrometry along with basic CSF parameters of ten adult patients with SMA types II or III before and after ten months of nusinersen therapy, in comparison with ten age- and gender-matched controls. These data were bioinformatically analyzed and correlated with clinical outcomes assessed by the Hammersmith Functional Rating Scale Expanded (HFMSE). Results: CSF proteomic profiles of patients with SMA differed from controls. Two groups of SMA patients were identified based on unsupervised clustering. These groups differed in age and expression of proteins related to neuroregeneration or neurodegeneration. Intraindividual CSF differences in response to nusinersen treatment varied between patients who clinically improved and those who did not. Conclusions: Comparative CSF proteomic analysis in adult SMA patients before and after treatment identified subgroups and treatment-related changes and may therefore be suitable for diagnostic and predictive analysis. These results require verification in larger multicenter cohorts.

2019-12-18 | PXD015117 | Pride

Cell-mediated cytotoxicity surrounding the brain in spinal muscular atrophy

Project description:We here longitudinally investigated how spinal muscular atrophy (SMA) and nusinersen shaped local immune responses in the cerebrospinal fluid (CSF).

2024-04-20 | PXD051600 | Pride

Gene expression profiling of LMC and MMC motor neurons in SMA mice

Project description:Spinal muscular atrophy (SMA) is a neurodegenerative disease which exhibits selective motor neuron death caused by a ubiquitous deficiency of the survival motor neuron (SMN) protein. It remains unclear how the ubiquitous reduction of SMN lead to death in selective motor neuron pools. Medial motor neuron columns (MMC) are vulnerable, whereas lateral motor columns (LMC) are resistant to motor neuron death in SMA. Here we performed microarray and pathway analysis comparing cholera toxin subunit B (CTb) labeled vulnerable MMC and resistant LMC of pre-symptomatic SMA with corresponding motor neuron columns of control mice to identify pathways involved in selective motor neuron death in SMA. WT is FVB. SMN is Delta7 (SMNΔ7;SMN2;Smn-) on a FVB background.

2017-12-12 | GSE81245 | GEO

Global gene expression profile and splicing events of iPS-derived motorneurons from SMA patient, unaffected father and TGC-treated cells

Project description:Spinal Muscular Atrophy (SMA) is an autosomal recessive motor neuron disease and is the second most common genetic disorder leading to death in childhood. Motoneurons derived from induced pluripotent stem cells (iPSC) obtained by reprogramming SMA patient and his healthy father fibroblasts, and genetically corrected SMA-iPSC obtained converting SMN2 into SMN1 with target gene correction (TGC), were used to study gene expression and splicing events linked to pathogenetic mechanisms. Microarray technology was used to assess the global gene expression profile as well as splicing events of iPS-derived motorneurons from SMA patient, unaffected father and TGC-treated cells. The microarray data derived from three different groups: SMA patient, healty father and treated SMA patient's cells. Each population consists of three RNA profiling cell samples.

2013-01-04 | E-GEOD-27205 | biostudies-arrayexpress

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