Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model

Hua, Yimin; Sahashi, Kentaro; Rigo, Frank; Hung, Gene; Horev, Guy; Bennett, C. Frank; Krainer, Adrian R.

doi:10.1038/nature10485

Cited by 643 publications

(707 citation statements)

References 30 publications

Supporting

Mentioning

675

Contrasting

Unclassified

Order By: Relevance

“…18,[53][54][55][56] We aimed to test a situation suitable for future patient care and chose oral application beginning on the first day of life (P0). Protein analysis of SMA animals at different disease stages demonstrates that there may be organ as well as time-dependent effects of HDACi treatment on SMN levels.…”

Section: Discussionmentioning

confidence: 99%

“…40 Disturbance of the insulin-like growth factor 1 axis has been proposed as explanation for the dwarf-like phenotype of older animals. 18,58,59 It is possible that the gastrointestinal involvement at least contributes to the diminished growth in SMA animals and impedes effective oral drug treatment in later stages of the disease. Diarrhea or fluid in the abdomen are not commonly described features of SMA in human, but reflux esophagitis is a known feature.…”

Section: Discussionmentioning

confidence: 99%

“…5 A therapy leading to reliable upregulation of SMN2 transcription can therefore be expected to be effective in most SMA patients. Hence, many therapeutic strategies have been suggested and reported, including: (i) elevation of SMN2 RNA and protein levels by transcription activation, correction of SMN2 splicing or stabilization of protein using drugs or antisense oligos, (ii) gene replacement by gene therapy approaches, (iii) neuroprotective therapy and (iv) stem cell therapy (reviewed in [15][16][17]18 ). Despite these promising experimental approaches, no readily available effective treatment for SMA exists to date.…”

Section: Introductionmentioning

confidence: 99%

“…30 Recent reports suggest that abnormal heart development in mice and human [41][42][43][44] as well as defects in skeletal muscle 45 and skeletal muscle vasculature 46 of mice are part of the phenotype and that SMA may be not a pure motoneuron disease. In addition, decreased levels of hepatic insulin-like growth factor binding protein acid labile subunit 18 possibly account for some of the dwarfism observed consistently across different SMA mouse models. Here, we show that SMA mice exhibit abnormalities of several internal organs, particularly lung, intestine and heart as well as skeletal muscle capillary defects.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

et al. 2012

View full text Add to dashboard Cite

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 a-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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2012

View full text Add to dashboard Cite

show abstract

“…However, in the last 5 years, a number of studies have highlighted abnormalities in other cell types in SMA (reviewed in5, 6). In addition, studies have highlighted the benefit of systemic delivery of therapeutic compounds when compared to CNS restricted delivery on the phenotypic amelioration in preclinical studies 7, 8. Altogether, SMA is emerging as a multi‐organ disorder rather than simply a motor neuron disease per se.…”

Section: Spinal Muscular Atrophy As a Multi‐organ Disordermentioning

confidence: 99%

New insights into SMA pathogenesis: immune dysfunction and neuroinflammation

Deguise

Kothary

2017

Ann Clin Transl Neurol

View full text Add to dashboard Cite

Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by motor neuron degeneration, although defects in multiple cell types and tissues have also been implicated. Three independent laboratories recently identified immune organ defects in SMA. We therefore propose a novel pathogenic mechanism contributory to SMA, resulting in higher susceptibility to infection and exacerbated disease progression caused by neuroinflammation. Overall, compromised immune function could significantly affect survival and quality of life of SMA patients. We highlight the recent findings in immune organ defects, their potential consequences on patients, our understanding of neuroinflammation in SMA, and new research hypotheses in SMA pathogenesis.

show abstract