Spinal Muscular atrophy therapeutics development in SMA: Difference between revisions
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'''Histone deacetylase inhibitors''' | '''Histone deacetylase inhibitors'''. | ||
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*''''Aminoglycosides'''' appear to promote read-through of the [[stop codon]] and thereby stabilize the [[SMN]] protein (Wolstencraft 2005). | *''''Aminoglycosides'''' appear to promote read-through of the [[stop codon]] and thereby stabilize the [[SMN]] protein (Wolstencraft 2005). | ||
*''''[[Riluzole]] and [[Gabapentin]]'''' | *''''[[Riluzole]] and [[Gabapentin]]'''' | ||
*''''[[NMDA receptor activation]]'''' | *''''[[NMDA receptor activation]]'''' | ||
*''''[[Antisense oligonucleotides]]'''' ([[ASO]]) have been shown to prevent skipping of [[exon]] 7, that in turn enhances production of full-length SMN [[mRNA]] in [[fibroblasts]] from patients | *''''[[Antisense oligonucleotides]]'''' ([[ASO]]) have been shown to prevent skipping of [[exon]] 7, that in turn enhances production of full-length SMN [[mRNA]] in [[fibroblasts]] from patients <ref name="pmid19430205">{{cite journal| author=Singh NN, Shishimorova M, Cao LC, Gangwani L, Singh RN| title=A short antisense oligonucleotide masking a unique intronic motif prevents skipping of a critical exon in spinal muscular atrophy. | journal=RNA Biol | year= 2009 | volume= 6 | issue= 3 | pages= 341-50 | pmid=19430205 | doi= | pmc=PMC2734876 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19430205 }} </ref> | ||
*''''[[Stem cells therapy]]'''' - [[Pluripotent]] stem cells with the capacity to differentiate into motor neurons could serve as an important model system <ref name="pmid19098894">{{cite journal| author=Ebert AD, Yu J, Rose FF, Mattis VB, Lorson CL, Thomson JA et al.| title=Induced pluripotent stem cells from a spinal muscular atrophy patient. | journal=Nature | year= 2009 | volume= 457 | issue= 7227 | pages= 277-80 | pmid=19098894 | doi=10.1038/nature07677 | pmc=PMC2659408 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19098894 }} </ref>. | *''''[[Stem cells therapy]]'''' - [[Pluripotent]] stem cells with the capacity to differentiate into motor neurons could serve as an important model system <ref name="pmid19098894">{{cite journal| author=Ebert AD, Yu J, Rose FF, Mattis VB, Lorson CL, Thomson JA et al.| title=Induced pluripotent stem cells from a spinal muscular atrophy patient. | journal=Nature | year= 2009 | volume= 457 | issue= 7227 | pages= 277-80 | pmid=19098894 | doi=10.1038/nature07677 | pmc=PMC2659408 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19098894 }} </ref>. | ||
*''''[[Gene therapy]]'''' <ref name="pmid20190738">{{cite journal| author=Foust KD, Wang X, McGovern VL, Braun L, Bevan AK, Haidet AM et al.| title=Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN. | journal=Nat Biotechnol | year= 2010 | volume= 28 | issue= 3 | pages= 271-4 | pmid=20190738 | doi=10.1038/nbt.1610 | pmc=PMC2889698 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20190738 }} </ref> | *''''[[Gene therapy]]'''' <ref name="pmid20190738">{{cite journal| author=Foust KD, Wang X, McGovern VL, Braun L, Bevan AK, Haidet AM et al.| title=Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN. | journal=Nat Biotechnol | year= 2010 | volume= 28 | issue= 3 | pages= 271-4 | pmid=20190738 | doi=10.1038/nbt.1610 | pmc=PMC2889698 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20190738 }} </ref> | ||
Revision as of 20:18, 24 June 2011
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
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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-
- 'Albuterol', a beta-adrenergic agonist already widely used in treatment of Asthma.
- 'Indoprofen' is a Non-steroidal anti-inflammatory drug.
Other approaches-
- 'Aminoglycosides' appear to promote read-through of the stop codon and thereby stabilize the SMN protein (Wolstencraft 2005).
- 'Riluzole and Gabapentin'
- 'Antisense oligonucleotides' (ASO) have been shown to prevent skipping of exon 7, that in turn enhances production of full-length SMN mRNA in fibroblasts from patients [1]
- 'Stem cells therapy' - Pluripotent stem cells with the capacity to differentiate into motor neurons could serve as an important model system [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.
- ↑ 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.
- ↑ 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.