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 journalArticle

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Abstract

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.
Volume21
Issue number6
Early online date17 Oct 2012
DOIs
Publication statusPublished - Jun 2013

Fingerprint

Spinal Muscular Atrophy
Histone Deacetylase Inhibitors
Therapeutics
JNJ 26481585
Valproic Acid
Motor Neurons
Standard of Care
Sudden Death
Pharmaceutical Preparations
Intestines
Autopsy
Myocardium
Skeletal Muscle
Fibroblasts
Clinical Trials
Phenotype
Weights and Measures
Cell Line
Lung

Keywords

  • 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

Cite this

Severe SMA mice show organ impairment that cannot be rescued by therapy with the HDACi JNJ-26481585. / Schreml, Julia; Riessland, Markus; Paterno, Mario; Garbes, Lutz; Roßbach, Kristina; Ackermann, Bastian; Krämer, Jan; Somers, Eilidh; Parson, Simon H; Heller, Raoul; Berkessel, Albrecht; Sterner-Kock, Anja; Wirth, Brunhilde.

In: EJHG : European journal of human genetics : the official journal of the European Society of Human Genetics. , Vol. 21, No. 6, 06.2013, p. 643-652.

Research output: Contribution to journalArticle

Schreml, J, Riessland, M, Paterno, M, Garbes, L, Roßbach, K, Ackermann, B, Krämer, J, Somers, E, Parson, SH, Heller, R, Berkessel, A, Sterner-Kock, A & Wirth, B 2013, 'Severe SMA mice show organ impairment that cannot be rescued by therapy with the HDACi JNJ-26481585' EJHG : European journal of human genetics : the official journal of the European Society of Human Genetics. , vol. 21, no. 6, pp. 643-652. https://doi.org/10.1038/ejhg.2012.222
Schreml, Julia ; Riessland, Markus ; Paterno, Mario ; Garbes, Lutz ; Roßbach, Kristina ; Ackermann, Bastian ; Krämer, Jan ; Somers, Eilidh ; Parson, Simon H ; Heller, Raoul ; Berkessel, Albrecht ; Sterner-Kock, Anja ; Wirth, Brunhilde. / Severe SMA mice show organ impairment that cannot be rescued by therapy with the HDACi JNJ-26481585. In: EJHG : European journal of human genetics : the official journal of the European Society of Human Genetics. . 2013 ; Vol. 21, No. 6. pp. 643-652.
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AU - Roßbach, Kristina

AU - Ackermann, Bastian

AU - Krämer, Jan

AU - Somers, Eilidh

AU - Parson, Simon H

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