Valproic acid increases SMN2 expression and modulates SF2/ASF and hnRNPA1 expression in SMA fibroblast cell lines

Harahap, Indra Sari Kusuma; Saitô, Toshio; San, Lai Poh; Sasaki, Naoki; Gunadi, Gunadi; Nurputra, Dian Kesumapramudya; Yusoff, Surini; Yamamoto, Tomoto; Morikawa, Satoru; Nishimura, Noriyuki; Lee, Myeong Jin; Takeshima, Yasuhiro; Matsuo, Masafumi; Nishio, Hisahide

doi:10.1016/j.braindev.2011.04.010

Cited by 35 publications

(31 citation statements)

References 58 publications

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“…Lower SMN2 copy numbers and lower SMN protein levels were found to be associated with an increased susceptibility to and severity of ALS Veldink et al, 2005). In SMA fibroblast cultures, VPA administration activated SMN2 transcription, modulated the expression of splicing factors (Harahap et al, 2012), and increased the expression of SMN protein (Sumner et al, 2003). The upregulated level of SMN protein has also been shown to depend on the number of SMN2 copies (Brichta et al, 2003).…”

Section: E Alsmentioning

confidence: 95%

Therapeutic Potential of Mood Stabilizers Lithium and Valproic Acid: Beyond Bipolar Disorder

et al. 2013

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Section: E Alsmentioning

confidence: 95%

Therapeutic Potential of Mood Stabilizers Lithium and Valproic Acid: Beyond Bipolar Disorder

et al. 2013

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“…The antihypertensive drug amiloride and its analog 5-(N-ethyl-N-isopropyl)amiloride increase expression of SMN2 protein in SMA cells by increasing inclusion of exon 7 , as does valproic acid (Harahap et al, 2012). A number of histone deacetylase inhibitors increase the lifespan of SMA mice (Wirth et al, 2006).…”

Section: Drug Design Directly Targeting Aberrant Splicing or Suppressmentioning

confidence: 99%

mRNA Transcript Diversity Creates New Opportunities for Pharmacological Intervention

Barrie

Smith²,

Sanford³

et al. 2012

Mol Pharmacol

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Most protein coding genes generate multiple RNA transcripts through alternative splicing, variable 3Ј and 5ЈUTRs, and RNA editing. Although drug design typically targets the main transcript, alternative transcripts can have profound physiological effects, encoding proteins with distinct functions or regulatory properties. Formation of these alternative transcripts is tissueselective and context-dependent, creating opportunities for more effective and targeted therapies with reduced adverse effects. Moreover, genetic variation can tilt the balance of alternative versus constitutive transcripts or generate aberrant transcripts that contribute to disease risk. In addition, environmental factors and drugs modulate RNA splicing, affording new opportunities for the treatment of splicing disorders. For example, therapies targeting specific mRNA transcripts with splicesite-directed oligonucleotides that correct aberrant splicing are already in clinical trials for genetic disorders such as Duchenne muscular dystrophy. High-throughput sequencing technologies facilitate discovery of novel RNA transcripts and protein isoforms, applications ranging from neuromuscular disorders to cancer. Consideration of a gene's transcript diversity should become an integral part of drug design, development, and therapy.

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“…A more recent study testing the efficacy of 3 in vitro confirmed an increase in total SMN2 mRNA, but reported no change in exon 7 inclusion levels. 52 An in vivo test of 3 efficacy in homozygous 5058 SMA mice resulted in a 100% increase in median survival, a slight increase in SMN protein in the spinal cord, and improvements in muscle and neuron pathology. 53 However, the authors noted decreases in growth cone size, axon length, motor neuron survival, and increased excitability in axon terminals, which suggested that 3 might be detrimental to motor neuron survival and function.…”

Section: Repurposed Drugsmentioning

confidence: 99%

Small Molecules in Development for the Treatment of Spinal Muscular Atrophy

2016

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Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease resulting from pathologically low levels of survival motor neuron (SMN) protein. The majority of mRNA from the SMN2 allele undergoes alternative splicing and excludes critical codons, causing an SMN protein deficiency. While there is currently no FDA-approved treatment for SMA, early therapeutic efforts have focused on testing repurposed drugs such as phenylbutyrate (2), valproic acid (3), riluzole (6), hydroxyurea (7), and albuterol (9), none of which has demonstrated clinical effectiveness. More recently, clinical trials have focused on novel small-molecule compounds identified from high-throughput screening and medicinal chemistry optimization such as olesoxime (11), CK-2127107, RG7800, LMI070, and RG3039 (17). In this paper, we review both repurposed drugs and small-molecule compounds discovered following medicinal chemistry optimization for the potential treatment of SMA.

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Valproic acid increases SMN2 expression and modulates SF2/ASF and hnRNPA1 expression in SMA fibroblast cell lines

Cited by 35 publications

References 58 publications

Therapeutic Potential of Mood Stabilizers Lithium and Valproic Acid: Beyond Bipolar Disorder

Therapeutic Potential of Mood Stabilizers Lithium and Valproic Acid: Beyond Bipolar Disorder

mRNA Transcript Diversity Creates New Opportunities for Pharmacological Intervention

Small Molecules in Development for the Treatment of Spinal Muscular Atrophy

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