Severe SMA mice show organ impairment that cannot be rescued by therapy with the HDACi JNJ-26481585.
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.
Institute of Human Genetics, University of Cologne, Cologne, Germany.
Julia
J
Schreml
Markus
M
Riessland
Mario
M
Paterno
Lutz
L
Garbes
Kristina
K
Roßbach
Bastian
B
Ackermann
Jan
J
Krämer
Eilidh
E
Somers
Simon H
SH
Parson
Raoul
R
Heller
Albrecht
A
Berkessel
Anja
A
Sterner-Kock
Brunhilde
B
Wirth
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D006877:Hydroxamic Acids / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D018482:Muscle, Skeletal / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D009469:Neuromuscular Junction / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009928:Organ Specificity / Q000187:drug effects; D010641:Phenotype; D055532:SMN Complex Proteins / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016019:Survival Analysis; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects
D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D055532:SMN Complex Proteins; C541788:quisinostat