The oral splicing modifier RG7800 increases full length survival of motor neuron 2 mRNA and survival of motor neuron protein: Results from trials in healthy adults and patients with spinal muscular atrophy

Heidemarie Kletzl, Anne Marquet, Andreas Günther, Wakana Tang, Jules Heuberger, Geert Jan Groeneveld, Willem Birkhoff, Eugenio Mercuri, Hanns Lochmüller, Claire Wood, Dirk Fischer, Irene Gerlach, Katja Heinig, Teodorica Bugawan, Sebastian Dziadek, Russell Kinch, Christian Czech, Omar Khwaja

Research output: Contribution to journalArticle

Abstract

Spinal muscular atrophy (SMA) is a rare genetic and progressively debilitating neuromuscular disease. It is the leading genetic cause of death among infants. In SMA, low levels of survival of motor neuron (SMN) protein lead to motor neuron death and muscle atrophy as the SMN protein is critical to motor neuron survival. SMA is caused by mutations in, or deletion of, the SMN1 gene. A second SMN gene, SMN2, produces only low levels of functional SMN protein due to alternative splicing which excludes exon 7 from most transcripts, generating truncated, rapidly degraded SMN protein. Patients with SMA rely on limited expression of functional SMN full-length protein from the SMN2 gene, but insufficient levels are generated. RG7800 is an oral, selective SMN2 splicing modifier designed to modulate alternative splicing of SMN2 to increase the levels of functional SMN protein. In two trials, oral administration of RG7800 increased in blood full-length SMN2 mRNA expression in healthy adults and SMN protein levels in SMA patients by up to two-fold, which is expected to provide clinical benefit.

Original languageEnglish
JournalNeuromuscular Disorders
DOIs
Publication statusAccepted/In press - Jan 1 2018

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Keywords

  • Neuromuscular disease
  • SMN protein
  • SMN2 splicing modifier
  • Spinal muscular atrophy
  • Survival of motor neuron

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Neurology
  • Clinical Neurology
  • Genetics(clinical)

Cite this

Kletzl, H., Marquet, A., Günther, A., Tang, W., Heuberger, J., Groeneveld, G. J., Birkhoff, W., Mercuri, E., Lochmüller, H., Wood, C., Fischer, D., Gerlach, I., Heinig, K., Bugawan, T., Dziadek, S., Kinch, R., Czech, C., & Khwaja, O. (Accepted/In press). The oral splicing modifier RG7800 increases full length survival of motor neuron 2 mRNA and survival of motor neuron protein: Results from trials in healthy adults and patients with spinal muscular atrophy. Neuromuscular Disorders. https://doi.org/10.1016/j.nmd.2018.10.001