Nusinersen: A Treatment for Spinal Muscular Atrophy

Claborn, Melanie K; Stevens, Debra L; Walker, Cheri; Gildon, Brooke L.

doi:10.1177/1060028018789956

Cited by 58 publications

(44 citation statements)

References 30 publications

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“…Splice-switching antisense oligonucleotides (ASOs) have proven to be effective therapeutic modulators of pre-mRNA splicing in a target-specific manner ( 19–21 ). ASOs are short, chemically modified oligonucleotides that bind to a target sequence through complementary, anti-parallel base-pairing.…”

Section: Introductionmentioning

confidence: 99%

Antisense oligonucleotide-mediated correction of CFTR splicing improves chloride secretion in cystic fibrosis patient-derived bronchial epithelial cells

Michaels

Bridges

Hastings

2020

Nucleic Acids Research

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Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, encoding an anion channel that conducts chloride and bicarbonate across epithelial membranes. Mutations that disrupt pre-mRNA splicing occur in >15% of CF cases. One common CFTR splicing mutation is CFTR c.3718-2477C>T (3849+10 kb C>T), which creates a new 5′ splice site, resulting in splicing to a cryptic exon with a premature termination codon. Splice-switching antisense oligonucleotides (ASOs) have emerged as an effective therapeutic strategy to block aberrant splicing. We test an ASO targeting the CFTR c.3718-2477C>T mutation and show that it effectively blocks aberrant splicing in primary bronchial epithelial (hBE) cells from CF patients with the mutation. ASO treatment results in long-term improvement in CFTR activity in hBE cells, as demonstrated by a recovery of chloride secretion and apical membrane conductance. We also show that the ASO is more effective at recovering chloride secretion in our assay than ivacaftor, the potentiator treatment currently available to these patients. Our findings demonstrate the utility of ASOs in correcting CFTR expression and channel activity in a manner expected to be therapeutic in patients.

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Section: Introductionmentioning

confidence: 99%

Antisense oligonucleotide-mediated correction of CFTR splicing improves chloride secretion in cystic fibrosis patient-derived bronchial epithelial cells

Michaels

Bridges

Hastings

2020

Nucleic Acids Research

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“…These therapies have shown promise in animal studies [24,25] and safety in human clinical trials [26]. In addition, delivery in the CSF is a minimally invasive surgical intervention with a lower risk to the patient than other surgical interventions such as convection enhanced drug delivery and deep brain stimulation [25,27,28].…”

Section: Introductionmentioning

confidence: 99%

Characterization of intrathecal cerebrospinal fluid geometry and dynamics in cynomolgus monkeys (macaca fascicularis) by magnetic resonance imaging

et al. 2019

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Recent advancements have been made toward understanding the diagnostic and therapeutic potential of cerebrospinal fluid (CSF) and related hydrodynamics. Increased understanding of CSF dynamics may lead to improved detection of central nervous system (CNS) diseases and optimized delivery of CSF based CNS therapeutics, with many proposed therapeutics hoping to successfully treat or cure debilitating neurological conditions. Before significant strides can be made toward the research and development of interventions designed for human use, additional research must be carried out with representative subjects such as non-human primates (NHP). This study presents a geometric and hydrodynamic characterization of CSF in eight cynomolgus monkeys ( Macaca fascicularis ) at baseline and two-week follow-up. Results showed that CSF flow along the entire spine was laminar with a Reynolds number ranging up to 80 and average Womersley number ranging from 4.1–7.7. Maximum CSF flow rate occurred ~25 mm caudal to the foramen magnum. Peak CSF flow rate ranged from 0.3–0.6 ml/s at the C3-C4 level. Geometric analysis indicated that average intrathecal CSF volume below the foramen magnum was 7.4 ml. The average surface area of the spinal cord and dura was 44.7 and 66.7 cm 2 respectively. Subarachnoid space cross-sectional area and hydraulic diameter ranged from 7–75 mm 2 and 2–3.7 mm, respectively. Stroke volume had the greatest value of 0.14 ml at an axial location corresponding to C3-C4.

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“…Usually, SMA is caused by a homozygous deletion of the SMN1 gene, resulting in SMN protein de iciency. The SMN locus contains a paralog SMN2 due to an inverted duplication on human chromosome 5 [4].…”

Section: Discussionmentioning

confidence: 99%

Novel Complication of Nusinersen Treatment: Hyponatremia

Çoban¹

2018

J Clin Intensive Care Med

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There are variations in therapeutic regimens of different liver diseases. The accurate diagnosis ensNusinersen treatment is a novel therapy for spinal muscular atrophy (SMA) type 1; consequently, the adverse reactions of the therapy, have not been well known, yet. The present study is a case report that declares a hyponatremia development after the nursinersen therapy. Since the therapy is quite new one and has limited practice, we hope that this rare complication will contribute to the scientifi c literature.

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Nusinersen: A Treatment for Spinal Muscular Atrophy

Abstract: Nusinersen is safe and effective in patients with SMA. It was well tolerated across all studied age groups.

Cited by 58 publications

References 30 publications

Antisense oligonucleotide-mediated correction of CFTR splicing improves chloride secretion in cystic fibrosis patient-derived bronchial epithelial cells

Antisense oligonucleotide-mediated correction of CFTR splicing improves chloride secretion in cystic fibrosis patient-derived bronchial epithelial cells

Characterization of intrathecal cerebrospinal fluid geometry and dynamics in cynomolgus monkeys (macaca fascicularis) by magnetic resonance imaging

Novel Complication of Nusinersen Treatment: Hyponatremia

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