Severe SMA mice show organ impairment that cannot be rescued by therapy with the HDACi JNJ-26481585

Julia Schreml, Markus Riessland, Mario Paterno, Lutz Garbes, Kristina Roßbach, Bastian Ackermann, Jan Krämer, Eilidh Somers, Simon H Parson, Raoul Heller, Albrecht Berkessel, Anja Sterner-Kock, Brunhilde Wirth

Research output: Contribution to journalArticlepeer-review

62 Citations (Scopus)


Spinal muscular atrophy (SMA) is the leading genetic cause of early childhood death worldwide and no therapy is available today. Many drugs, especially histone deacetylase inhibitors (HDACi), increase SMN levels. As all HDACi tested so far only mildly ameliorate the SMA phenotype or are unsuitable for use in humans, there is still need to identify more potent drugs. Here, we assessed the therapeutic power of the pan-HDACi JNJ-26481585 for SMA, which is currently used in various clinical cancer trials. When administered for 64 h at 100 nM, JNJ-26481585 upregulated SMN levels in SMA fibroblast cell lines, including those from non-responders to valproic acid. Oral treatment of Taiwanese SMA mice and control littermates starting at P0 showed no overt extension of lifespan, despite mild improvements in motor abilities and weight progression. Many treated and untreated animals showed a very rapid decline or unexpected sudden death. We performed exploratory autopsy and histological assessment at different disease stages and found consistent abnormalities in the intestine, heart and lung and skeletal muscle vasculature of SMA animals, which were not prevented by JNJ-26481585 treatment. Interestingly, some of these features may be only indirectly caused by α-motoneuron function loss but may be major life-limiting factors in the course of disease. A better understanding of - primary or secondary - non-neuromuscular organ involvement in SMA patients may improve standard of care and may lead to reassessment of how to investigate SMA patients clinically.

Original languageEnglish
Pages (from-to)643-652
Number of pages10
JournalEJHG : European journal of human genetics : the official journal of the European Society of Human Genetics.
Issue number6
Early online date17 Oct 2012
Publication statusPublished - Jun 2013


  • Animals
  • Body Weight
  • Brain
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Fibroblasts
  • Histone Deacetylase Inhibitors
  • Humans
  • Hydroxamic Acids
  • Mice
  • Motor Activity
  • Muscle, Skeletal
  • Muscular Atrophy, Spinal
  • Neuromuscular Junction
  • Organ Specificity
  • Phenotype
  • SMN Complex Proteins
  • Spinal Cord
  • Survival Analysis
  • Treatment Outcome
  • Up-Regulation


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