Nusinersen: antisense oligonucleotide to increase SMN protein production in spinal muscular atrophy

2017 ◽  
Vol 53 (6) ◽  
pp. 327 ◽  
Author(s):  
D.M. Paton
Keyword(s):  
Spinal Muscular Atrophy ◽  
Antisense Oligonucleotide ◽  
Protein Production ◽  
Muscular Atrophy ◽  
Smn Protein

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

2021 ◽  
Vol 11 (3) ◽  
pp. 296
Author(s):  
Lars Hendrik Müschen ◽  
Alma Osmanovic ◽  
Camilla Binz ◽  
Konstantin F. Jendretzky ◽  
Gresa Ranxha ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Spinal Muscular Atrophy ◽  
Total Protein ◽  
Antisense Oligonucleotide ◽  
Muscular Atrophy ◽  
Neurological Diseases ◽  
Clinical Signs ◽  
Central Nervous System Disease ◽  
Oligoclonal Bands ◽  
System Disease

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.

SMN mRNA and protein levels in peripheral blood

Neurology ◽  
2006 ◽  
Vol 66 (7) ◽  
pp. 1067-1073 ◽  
Author(s):  
C. J. Sumner ◽  
S. J. Kolb ◽  
G. G. Harmison ◽  
N. O. Jeffries ◽  
K. Schadt ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Spinal Muscular Atrophy ◽  
Disease Severity ◽  
Peripheral Blood ◽  
Muscular Atrophy ◽  
Gene Copy ◽  
Blood Levels ◽  
Type I ◽  
Protein Levels ◽  
Smn Protein

Background: Clinical trials of drugs that increase SMN protein levels in vitro are currently under way in patients with spinal muscular atrophy.Objective: To develop and validate measures of SMN mRNA and protein in peripheral blood and to establish baseline SMN levels in a cohort of controls, carriers, and patients of known genotype, which could be used to follow response to treatment.Methods: SMN1 and SMN2 gene copy numbers were determined in blood samples collected from 86 subjects. Quantitative reverse transcription PCR was used to measure blood levels of SMN mRNA with and without exon 7. A cell immunoassay was used to measure blood levels of SMN protein.Results: Blood levels of SMN mRNA and protein were measured with high reliability. There was little variation in SMN levels in individual subjects over a 5-week period. Levels of exon 7-containing SMN mRNA and SMN protein correlated with SMN1 and SMN2 gene copy number. With the exception of type I SMA, there was no correlation between SMN levels and disease severity.Conclusion: SMN mRNA and protein levels can be reliably measured in the peripheral blood and used during clinical trials in spinal muscular atrophy, but these levels do not necessarily predict disease severity.

scholarly journals Calpain Inhibition Increases SMN Protein in Spinal Cord Motoneurons and Ameliorates the Spinal Muscular Atrophy Phenotype in Mice

2018 ◽  
Vol 56 (6) ◽  
pp. 4414-4427 ◽  
Author(s):  
Sandra de la Fuente ◽  
Alba Sansa ◽  
Ambika Periyakaruppiah ◽  
Ana Garcera ◽  
Rosa M. Soler
Keyword(s):  
Spinal Cord ◽  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Smn Protein ◽  
Calpain Inhibition

scholarly journals Antisense Oligonucleotide Therapies for Neurodegenerative Diseases

2019 ◽  
Vol 42 (1) ◽  
pp. 385-406 ◽  
Author(s):  
C. Frank Bennett ◽  
Adrian R. Krainer ◽  
Don W. Cleveland
Keyword(s):  
Neurodegenerative Diseases ◽  
Spinal Muscular Atrophy ◽  
Antisense Oligonucleotide ◽  
Antisense Oligonucleotides ◽  
Muscular Atrophy ◽  
Neurological Diseases ◽  
Great Promise ◽  
Disease Symptoms ◽  
Therapeutic Platform ◽  
Lateral Sclerosis

Antisense oligonucleotides represent a novel therapeutic platform for the discovery of medicines that have the potential to treat most neurodegenerative diseases. Antisense drugs are currently in development for the treatment of amyotrophic lateral sclerosis, Huntington's disease, and Alzheimer's disease, and multiple research programs are underway for additional neurodegenerative diseases. One antisense drug, nusinersen, has been approved for the treatment of spinal muscular atrophy. Importantly, nusinersen improves disease symptoms when administered to symptomatic patients rather than just slowing the progression of the disease. In addition to the benefit to spinal muscular atrophy patients, there are discoveries from nusinersen that can be applied to other neurological diseases, including method of delivery, doses, tolerability of intrathecally delivered antisense drugs, and the biodistribution of intrathecal dosed antisense drugs. Based in part on the early success of nusinersen, antisense drugs hold great promise as a therapeutic platform for the treatment of neurological diseases.

scholarly journals Molecular Mechanisms of Neurodegeneration in Spinal Muscular Atrophy

2016 ◽  
Vol 10 ◽  
pp. JEN.S33122 ◽  
Author(s):  
Saif Ahmad ◽  
Kanchan Bhatia ◽  
Annapoorna Kannan ◽  
Laxman Gangwani
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Molecular Mechanisms ◽  
Muscular Atrophy ◽  
Survival Motor Neuron ◽  
Skeletal Muscle Atrophy ◽  
Spinal Motor Neurons ◽  
Low Levels ◽  
Smn Protein

Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease with a high incidence and is the most common genetic cause of infant mortality. SMA is primarily characterized by degeneration of the spinal motor neurons that leads to skeletal muscle atrophy followed by symmetric limb paralysis, respiratory failure, and death. In humans, mutation of the Survival Motor Neuron 1 (SMN1) gene shifts the load of expression of SMN protein to the SMN2 gene that produces low levels of full-length SMN protein because of alternative splicing, which are sufficient for embryonic development and survival but result in SMA. The molecular mechanisms of the (a) regulation of SMN gene expression and (b) degeneration of motor neurons caused by low levels of SMN are unclear. However, some progress has been made in recent years that have provided new insights into understanding of the cellular and molecular basis of SMA pathogenesis. In this review, we have briefly summarized recent advances toward understanding of the molecular mechanisms of regulation of SMN levels and signaling mechanisms that mediate neurodegeneration in SMA.

scholarly journals Temporal and tissue-specific variability of SMN protein levels in mouse models of spinal muscular atrophy

2018 ◽  
Vol 27 (16) ◽  
pp. 2851-2862 ◽  
Author(s):  
Ewout J N Groen ◽  
Elena Perenthaler ◽  
Natalie L Courtney ◽  
Crispin Y Jordan ◽  
Hannah K Shorrock ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Mouse Models ◽  
Muscular Atrophy ◽  
Tissue Specific ◽  
Protein Levels ◽  
Smn Protein
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