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Related Concept Videos

siRNA - Small Interfering RNAs02:30

siRNA - Small Interfering RNAs

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Small interfering RNAs, or siRNAs, are short regulatory RNA molecules that can silence genes post-transcriptionally, as well as the transcriptional level in some cases. siRNAs are important for protecting cells against viral infections and silencing transposable genetic elements.
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Alternative RNA splicing is the regulated splicing of exons and introns to produce different mature mRNAs from a single pre-mRNA. Unlike in constitutive splicing where a single gene produces a single type of mRNA, alternative splicing allows an organism to produce multiple proteins from a single gene and plays an important role in protein diversity.
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RNA interference (RNAi) is a cellular mechanism that inhibits gene expression by suppressing its transcription or activating the RNA degradation process. The mechanism was discovered by Andrew Fire and Craig Mello in 1998 in plants. Today, it is observed in almost all eukaryotes, including protozoa, flies, nematodes, insects, parasites, and mammals. This precise cellular mechanism of gene silencing has been developed into a technique that provides an efficient way to identify and determine the...
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Riboswitches are non-coding mRNA domains that regulate the transcription and translation of downstream genes without the help of proteins. Riboswitches bind directly to a metabolite and can form unique stem-loop or hairpin structures in response to the amount of the metabolite present. They have two distinct regions – a metabolite-binding aptamer and an expression platform.
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Related Experiment Video

Updated: Jan 11, 2026

Evaluation of Exon Inclusion Induced by Splice Switching Antisense Oligonucleotides in SMA Patient Fibroblasts
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Risdiplam: A Small Molecule mRNA Splice Modifier Approved to Treat SMA Disease.

Lutz Müller1, Björn Jacobsen1, Alexander Nürnberg1

  • 1F. Hoffmann-La Roche Ltd, Basel, Switzerland.

Toxicologic Pathology
|November 18, 2025
PubMed
Summary

Risdiplam, an mRNA splice modifier, has helped thousands with spinal muscular atrophy. Its nonclinical development faced toxicological hurdles, overcome by novel strategies leading to clinical success.

Keywords:
SMN2male germ cellsretinarisdiplamsecondary splice targetsspinal muscular atrophysplice modifier

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Characterizing Exon Skipping Efficiency in DMD Patient Samples in Clinical Trials of Antisense Oligonucleotides
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Last Updated: Jan 11, 2026

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Characterizing Exon Skipping Efficiency in DMD Patient Samples in Clinical Trials of Antisense Oligonucleotides
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Area of Science:

  • Pharmacology
  • Toxicology
  • Genetics

Background:

  • Risdiplam is the sole approved small molecule mRNA splice modifier.
  • It has been used therapeutically for over five years for spinal muscular atrophy (SMA).
  • Thousands of SMA patients have benefited from risdiplam treatment.

Purpose of the Study:

  • To review the nonclinical development of risdiplam.
  • To focus on toxicological characterization and histopathological findings in animal models.
  • To highlight strategies used to overcome developmental challenges.

Main Methods:

  • Review of nonclinical studies on risdiplam.
  • Analysis of toxicological data from animal studies.
  • Examination of histopathological features in treated animals.

Main Results:

  • Nonclinical development encountered significant toxicological challenges.
  • Innovative strategies were developed to address these challenges.
  • These strategies were crucial for the eventual clinical success of risdiplam.

Conclusions:

  • The nonclinical development of risdiplam demonstrates the successful navigation of complex toxicological issues.
  • Histopathological findings in animal studies informed safety assessments.
  • Overcoming nonclinical toxicity was key to risdiplam's therapeutic application in SMA.