Cargando…

RNA Targeting in Inherited Neuromuscular Disorders: Novel Therapeutic Strategies to Counteract Mis-Splicing

Neuromuscular disorders represent multifaceted abnormal conditions, with little or no cure, leading to patient deaths from complete muscle wasting and atrophy. Despite strong efforts in the past decades, development of effective treatments is still urgently needed. Advent of next-generation sequenci...

Descripción completa

Detalles Bibliográficos
Autores principales: Verdile, Veronica, Guizzo, Gloria, Ferrante, Gabriele, Paronetto, Maria Paola
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8616048/
https://www.ncbi.nlm.nih.gov/pubmed/34831073
http://dx.doi.org/10.3390/cells10112850
_version_ 1784604253713596416
author Verdile, Veronica
Guizzo, Gloria
Ferrante, Gabriele
Paronetto, Maria Paola
author_facet Verdile, Veronica
Guizzo, Gloria
Ferrante, Gabriele
Paronetto, Maria Paola
author_sort Verdile, Veronica
collection PubMed
description Neuromuscular disorders represent multifaceted abnormal conditions, with little or no cure, leading to patient deaths from complete muscle wasting and atrophy. Despite strong efforts in the past decades, development of effective treatments is still urgently needed. Advent of next-generation sequencing technologies has allowed identification of novel genes and mutations associated with neuromuscular pathologies, highlighting splicing defects as essential players. Deciphering the significance and relative contributions of defective RNA metabolism will be instrumental to address and counteract these malignancies. We review here recent progress on the role played by alternative splicing in ensuring functional neuromuscular junctions (NMJs), and its involvement in the pathogenesis of NMJ-related neuromuscular disorders, with particular emphasis on congenital myasthenic syndromes and muscular dystrophies. We will also discuss novel strategies based on oligonucleotides designed to bind their cognate sequences in the RNA or targeting intermediary of mRNA metabolism. These efforts resulted in several chemical classes of RNA molecules that have recently proven to be clinically effective, more potent and better tolerated than previous strategies.
format Online
Article
Text
id pubmed-8616048
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-86160482021-11-26 RNA Targeting in Inherited Neuromuscular Disorders: Novel Therapeutic Strategies to Counteract Mis-Splicing Verdile, Veronica Guizzo, Gloria Ferrante, Gabriele Paronetto, Maria Paola Cells Review Neuromuscular disorders represent multifaceted abnormal conditions, with little or no cure, leading to patient deaths from complete muscle wasting and atrophy. Despite strong efforts in the past decades, development of effective treatments is still urgently needed. Advent of next-generation sequencing technologies has allowed identification of novel genes and mutations associated with neuromuscular pathologies, highlighting splicing defects as essential players. Deciphering the significance and relative contributions of defective RNA metabolism will be instrumental to address and counteract these malignancies. We review here recent progress on the role played by alternative splicing in ensuring functional neuromuscular junctions (NMJs), and its involvement in the pathogenesis of NMJ-related neuromuscular disorders, with particular emphasis on congenital myasthenic syndromes and muscular dystrophies. We will also discuss novel strategies based on oligonucleotides designed to bind their cognate sequences in the RNA or targeting intermediary of mRNA metabolism. These efforts resulted in several chemical classes of RNA molecules that have recently proven to be clinically effective, more potent and better tolerated than previous strategies. MDPI 2021-10-22 /pmc/articles/PMC8616048/ /pubmed/34831073 http://dx.doi.org/10.3390/cells10112850 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Verdile, Veronica
Guizzo, Gloria
Ferrante, Gabriele
Paronetto, Maria Paola
RNA Targeting in Inherited Neuromuscular Disorders: Novel Therapeutic Strategies to Counteract Mis-Splicing
title RNA Targeting in Inherited Neuromuscular Disorders: Novel Therapeutic Strategies to Counteract Mis-Splicing
title_full RNA Targeting in Inherited Neuromuscular Disorders: Novel Therapeutic Strategies to Counteract Mis-Splicing
title_fullStr RNA Targeting in Inherited Neuromuscular Disorders: Novel Therapeutic Strategies to Counteract Mis-Splicing
title_full_unstemmed RNA Targeting in Inherited Neuromuscular Disorders: Novel Therapeutic Strategies to Counteract Mis-Splicing
title_short RNA Targeting in Inherited Neuromuscular Disorders: Novel Therapeutic Strategies to Counteract Mis-Splicing
title_sort rna targeting in inherited neuromuscular disorders: novel therapeutic strategies to counteract mis-splicing
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8616048/
https://www.ncbi.nlm.nih.gov/pubmed/34831073
http://dx.doi.org/10.3390/cells10112850
work_keys_str_mv AT verdileveronica rnatargetingininheritedneuromusculardisordersnoveltherapeuticstrategiestocounteractmissplicing
AT guizzogloria rnatargetingininheritedneuromusculardisordersnoveltherapeuticstrategiestocounteractmissplicing
AT ferrantegabriele rnatargetingininheritedneuromusculardisordersnoveltherapeuticstrategiestocounteractmissplicing
AT paronettomariapaola rnatargetingininheritedneuromusculardisordersnoveltherapeuticstrategiestocounteractmissplicing