Spinal muscular atrophy phenotype is ameliorated in human motor neurons by SMN increase via different novel RNA therapeutic approaches

Monica Nizzardo, Chiara Simone, Sara Dametti, Sabrina Salani, Gianna Ulzi, Serena Pagliarani, Federica Rizzo, Emanuele Frattini, Franco Pagani, Nereo Bresolin, Giacomo Comi, Stefania Corti

Research output: Contribution to journalArticle

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Abstract

Spinal muscular atrophy (SMA) is a primary genetic cause of infant mortality due to mutations in the Survival Motor Neuron (SMN) 1 gene. No cure is available. Antisense oligonucleotides (ASOs) aimed at increasing SMN levels from the paralogous SMN2 gene represent a possible therapeutic strategy. Here, we tested in SMA human induced pluripotent stem cells (iPSCs) and iPSC-differentiated motor neurons, three different RNA approaches based on morpholino antisense targeting of the ISSN-1, exon-specific U1 small nuclear RNA (ExSpeU1), and Transcription Activator-Like Effector-Transcription Factor (TALE-TF). All strategies act modulating SMN2 RNA: ASO affects exon 7 splicing, TALE-TF increase SMN2 RNA acting on the promoter, while ExSpeU1 improves pre-mRNA processing. These approaches induced up-regulation of full-length SMN mRNA and differentially affected the Delta-7 isoform: ASO reduced this isoform, while ExSpeU1 and TALE-TF increased it. All approaches upregulate the SMN protein and significantly improve the in vitro SMA motor neurons survival. Thus, these findings demonstrate that therapeutic tools that act on SMN2 RNA are able to rescue the SMA disease phenotype. Our data confirm the feasibility of SMA iPSCs as in vitro disease models and we propose novel RNA approaches as potential therapeutic strategies for treating SMA and other genetic neurological disorders.

Original languageEnglish
Article number11746
JournalScientific Reports
Volume5
DOIs
Publication statusPublished - Jun 30 2015

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Spinal Muscular Atrophy
Motor Neurons
RNA
Phenotype
Induced Pluripotent Stem Cells
Antisense Oligonucleotides
Transcription Factors
Exons
Protein Isoforms
Up-Regulation
Therapeutics
Morpholinos
Inborn Genetic Diseases
RNA Precursors
Infant Mortality
Muscular Diseases
Nervous System Diseases
Genes
Messenger RNA
Mutation

ASJC Scopus subject areas

  • General

Cite this

Spinal muscular atrophy phenotype is ameliorated in human motor neurons by SMN increase via different novel RNA therapeutic approaches. / Nizzardo, Monica; Simone, Chiara; Dametti, Sara; Salani, Sabrina; Ulzi, Gianna; Pagliarani, Serena; Rizzo, Federica; Frattini, Emanuele; Pagani, Franco; Bresolin, Nereo; Comi, Giacomo; Corti, Stefania.

In: Scientific Reports, Vol. 5, 11746, 30.06.2015.

Research output: Contribution to journalArticle

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