Spinal muscular atrophy therapeutics development

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Editors-in-Chief: C. Michael Gibson, M.S., M.D.; Priyamvada Singh, MBBS

Overview

SMA disease severity has been found to be inversely related to the number of SMN2 gene and the amount of SMN protein present. Efforts are being directed to develop agents that can increase the amount of SMN2 gene and the SMN proteins. Also, other approaches like stem cell therapy, gene therapy are active areas of research. There is no standard treatment of SMA till date. However, the recent developments in molecular genetics have helped in understanding the pathogenesis of the disease and raises hope for a future treatment. Below are the drugs that have been actively studied in animal models and various clinical trials.


Drugs that act by increasing SMN protein, number of SMN2 gene, number of nuclear gems

Histone deacetylase inhibitors.

  • 'Phenylbutyrate'
  • 'Valproic acid' - already widely used in treatment of Epilepsy
  • 'LBH589 (hydroxamic acid)', already widely used in cancer clinical trials

Non-histone deacetylase inhibitors, but that also affect SMN2 gene expression levels or promote inclusion of exon 7 are-

Other approaches-

  • 'Aminoglycosides' appear to promote read-through of the stop codon and thereby stabilize the SMN protein [1].

References

  1. Wolstencroft EC, Mattis V, Bajer AA, Young PJ, Lorson CL (2005). "A non-sequence-specific requirement for SMN protein activity: the role of aminoglycosides in inducing elevated SMN protein levels". Hum Mol Genet. 14 (9): 1199–210. doi:10.1093/hmg/ddi131. PMID 15790598.
  2. Singh NN, Shishimorova M, Cao LC, Gangwani L, Singh RN (2009). "A short antisense oligonucleotide masking a unique intronic motif prevents skipping of a critical exon in spinal muscular atrophy". RNA Biol. 6 (3): 341–50. PMC 2734876. PMID 19430205.
  3. Ebert AD, Yu J, Rose FF, Mattis VB, Lorson CL, Thomson JA; et al. (2009). "Induced pluripotent stem cells from a spinal muscular atrophy patient". Nature. 457 (7227): 277–80. doi:10.1038/nature07677. PMC 2659408. PMID 19098894.
  4. Foust KD, Wang X, McGovern VL, Braun L, Bevan AK, Haidet AM; et al. (2010). "Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN". Nat Biotechnol. 28 (3): 271–4. doi:10.1038/nbt.1610. PMC 2889698. PMID 20190738.

da:Spinal muskulær atrofi de:Spinale Muskelatrophie el:Νωτιαία μυϊκή ατροφία nl:Spinale Musculaire Atrofieën fi:Spinaaliset lihasatrofiat sv:Spinal muskelatrofi



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