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Related Experiment Video

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Evaluation of Exon Inclusion Induced by Splice Switching Antisense Oligonucleotides in SMA Patient Fibroblasts
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Exploring Splicing-Switching Molecules For Seckel Syndrome Therapy.

Daniela Scalet1, Dario Balestra1, Sara Rohban2

  • 1Department of Life Sciences and Biotechnology, Section of Biochemistry and Molecular Biology, University of Ferrara, Via Fossato di Mortara 74, 44121 Ferrara, Italy.

Biochimica Et Biophysica Acta. Molecular Basis of Disease
|September 19, 2016
PubMed
Summary

The ATR c.2101A>G mutation causes Seckel Syndrome by promoting exon skipping. RNA-based therapies, including antisense oligonucleotides and U1 snRNA, show promise in restoring normal ATR splicing and protein levels.

Keywords:
(up to 6) Seckel syndrome-1Antisense oligonucleotideExonic splicing silencercorrection approachesmodified U1snRNA

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Area of Science:

  • Genetics
  • Molecular Biology
  • RNA Therapeutics

Background:

  • Seckel Syndrome (SS) is an orphan disease linked to the ATR gene, crucial for DNA-damage response.
  • The synonymous c.2101A>G mutation in ATR is the first identified genetic cause of SS, primarily inducing exon 9 skipping via an unclear mechanism.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying the ATR c.2101A>G mutation's effect on splicing.
  • To identify and evaluate potential RNA-based therapeutic strategies for Seckel Syndrome.

Main Methods:

  • ATR minigene expression studies to assess exon 9 splicing efficiency.
  • Site-directed mutagenesis to strengthen or weaken splice sites and evaluate their impact.
  • Analysis of splicing silencer (ESS) and enhancer (ESE) elements.
  • Antisense oligonucleotide (AON) and U1 snRNA (U1) targeting strategies.
  • Lentivirus-mediated delivery in humanized mouse embryonic fibroblasts.

Main Results:

  • The c.2101A>G mutation significantly impairs exon 9 inclusion (6±1%) by weakening splice site definition.
  • The mutation strengthens an exonic splicing silencer (ESS) and weakens an exonic splicing enhancer (ESE).
  • AONATR and U1ATR therapies partially restored correct ATR splicing and protein levels in vitro and in vivo.

Conclusions:

  • The ATR c.2101A>G mutation causes Seckel Syndrome through aberrant splicing, driven by altered ESS/ESE activity.
  • RNA-based therapeutics, specifically AONs and U1 snRNA, represent promising strategies for Seckel Syndrome treatment.