Dataset Information

Nusinersen ameliorates motor function and prevents motoneuron Cajal body disassembly and abnormal poly(A) RNA distribution in a SMA mouse model.

ABSTRACT: Spinal muscular atrophy (SMA) is a devastating autosomal recessive neuromuscular disease characterized by degeneration of spinal cord alpha motor neurons (?MNs). SMA is caused by the homozygous deletion or mutation of the survival motor neuron 1 (SMN1) gene, resulting in reduced expression of SMN protein, which leads to ?MN degeneration and muscle atrophy. The majority of transcripts of a second gene (SMN2) generate an alternative spliced isoform that lacks exon 7 and produces a truncated nonfunctional form of SMN. A major function of SMN is the biogenesis of spliceosomal snRNPs, which are essential components of the pre-mRNA splicing machinery, the spliceosome. In recent years, new potential therapies have been developed to increase SMN levels, including treatment with antisense oligonucleotides (ASOs). The ASO-nusinersen (Spinraza) promotes the inclusion of exon 7 in SMN2 transcripts and notably enhances the production of full-length SMN in mouse models of SMA. In this work, we used the intracerebroventricular injection of nusinersen in the SMN?7 mouse model of SMA to evaluate the effects of this ASO on the behavior of Cajal bodies (CBs), nuclear structures involved in spliceosomal snRNP biogenesis, and the cellular distribution of polyadenylated mRNAs in ?MNs. The administration of nusinersen at postnatal day (P) 1 normalized SMN expression in the spinal cord but not in skeletal muscle, rescued the growth curve and improved motor behavior at P12 (late symptomatic stage). Importantly, this ASO recovered the number of canonical CBs in MNs, significantly reduced the abnormal accumulation of polyadenylated RNAs in nuclear granules, and normalized the expression of the pre-mRNAs encoding chondrolectin and choline acetyltransferase, two key factors for ?MN homeostasis. We propose that the splicing modulatory function of nusinersen in SMA ?MN is mediated by the rescue of CB biogenesis, resulting in enhanced polyadenylated pre-mRNA transcription and splicing and nuclear export of mature mRNAs for translation. Our results support that the selective restoration of SMN expression in the spinal cord has a beneficial impact not only on ?MNs but also on skeletal myofibers. However, the rescue of SMN expression in muscle appears to be necessary for the complete recovery of motor function.

SUBMITTER: Berciano MT

PROVIDER: S-EPMC7330045 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Nusinersen ameliorates motor function and prevents motoneuron Cajal body disassembly and abnormal poly(A) RNA distribution in a SMA mouse model.

Berciano María T MT Puente-Bedia Alba A Medina-Samamé Almudena A Rodríguez-Rey José C JC Calderó Jordi J Lafarga Miguel M Tapia Olga O

Scientific reports 20200701 1

Spinal muscular atrophy (SMA) is a devastating autosomal recessive neuromuscular disease characterized by degeneration of spinal cord alpha motor neurons (αMNs). SMA is caused by the homozygous deletion or mutation of the survival motor neuron 1 (SMN1) gene, resulting in reduced expression of SMN protein, which leads to αMN degeneration and muscle atrophy. The majority of transcripts of a second gene (SMN2) generate an alternative spliced isoform that lacks exon 7 and produces a truncated nonfun ...[more]

PMID: 32612161

Similar Datasets

Project description:BackgroundThe reimbursement for expensive medicines poses a growing challenge to healthcare worldwide. In order to increase its control over the costs of medicines, the Dutch government introduced the Coverage Lock (CL) policy in 2015. The CL postpones decisions regarding reimbursement of expensive medicines until detailed advice on i.e., cost-effectiveness has been given. The CL has been in place for six years, has raised many questions and concerns, but currently, no evaluation is known to the authors. A better understanding of the effects of the CL on all stakeholders involved may contribute to reflections on the CL process and help find ways to improve it. An evaluation of Dutch policy will also be relevant for other countries that aim to optimize reimbursement procedures for expensive treatments. To perform this evaluation, we focused on the CL procedure for the medicine nusinersen. Nusinersen is the first treatment for spinal muscular atrophy (SMA). Following EMA approval in May 2017, it was placed in the CL. The analysis of cost-effectiveness and added therapeutic value resulted in an advice for reimbursement limited to children younger than 9.5 years at the start of treatment; this was implemented from August 2018 onwards.MethodsQualitative stakeholder perspective analysis of the CL procedure focusing on nusinersen with 15 stakeholders.ResultsStakeholders raised key issues of the CL based on their experience with nusinersen: emotional impact of the CL, duration of the CL procedure, appropriateness of the CL procedure for different types of medicines, transparency of the CL, a wish for patient-centred decision-making and the lack of uniformity of access to expensive treatments.DiscussionStakeholders supported measures to control healthcare expenses and to ensure reasonable pricing. They considered the delay in access to therapies and lack of procedural transparency to be the main challenges to the CL. Stakeholders also agreed that the interests of patients deserve more attention in the practical implementation of the reimbursement decision. Stakeholders suggested a number of adjustments to improve the CL, such as a faster start with conditional reimbursement programs to ensure access and intensify European collaboration to speed up the assessment of the medicine.

Dataset Information

Nusinersen ameliorates motor function and prevents motoneuron Cajal body disassembly and abnormal poly(A) RNA distribution in a SMA mouse model.

Publications

Nusinersen ameliorates motor function and prevents motoneuron Cajal body disassembly and abnormal poly(A) RNA distribution in a SMA mouse model.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets