Guest guest Posted May 30, 2006 Report Share Posted May 30, 2006 Interesting abstract - re. next generation HDAC inhibitor drug - Benzamide M344 - ...per below, initial indications 7-fold increase in full length SMN protein production (VPA & others were 3 or 4 fold I think)...more reasons to be optimistic about the future of SMA therapeutic treatments...Mitch Hum Genet. 2006 May 25; [Epub ahead of print] Related Articles, Links The benzamide M344, a novel histone deacetylase inhibitor, significantly increases SMN2 RNA/protein levels in spinal muscular atrophy cells. Riessland M, Brichta L, Hahnen E, Wirth B. Institute of Human Genetics, Institute of Genetics, and Center for Molecular Medicine Cologne, University of Cologne, Kerpener Str. 34, 50931, Cologne, Germany, brunhilde.wirth@.... Proximal spinal muscular atrophy (SMA) is a common autosomal recessively inherited neuromuscular disorder causing infant death in half of all patients. Homozygous loss of the survival motor neuron 1 (SMN1) gene causes SMA, whereas the number of the SMN2 copy genes modulates the severity of the disease. Due to a silent mutation within an exonic splicing enhancer, SMN2 mainly produces alternatively spliced transcripts lacking exon 7 and only approximately 10% of a full-length protein identical to SMN1. However, SMN2 represents a promising target for an SMA therapy. The correct splicing of SMN2 can be efficiently restored by over-expression of the splicing factor Htra2-beta1 as well as by exogenous factors like drugs that inhibit histone deacetylases (HDACs). Here we show that the novel benzamide M344, an HDAC inhibitor, up-regulates SMN2 protein expression in fibroblast cells derived from SMA patients up to 7-fold after 64 h of treatment. Moreover, M344 significantly raises the total number of gems/nucleus as well as the number of nuclei that contain gems. This is the strongest in vitro effect of a drug on the SMN protein level reported so far. The reversion of Delta7-SMN2 into FL-SMN2 transcripts as demonstrated by quantitative RT-PCR is most likely facilitated by elevated levels of Htra2-beta1. Investigations of the cytotoxicity of M344 using an MTT assay revealed toxic cell effects only at very high concentrations. In conclusion, M344 can be considered as highly potent HDAC inhibitor which is active at low doses and therefore represents a promising candidate for a causal therapy of SMA. PMID: 16724231 [PubMed - as supplied by publisher __________________________________________________ Quote Link to comment Share on other sites More sharing options...
Guest guest Posted May 30, 2006 Report Share Posted May 30, 2006 Is it possible to get that drug now? These trials and waiting for results really get to me. We, the people who are adults living with SMA, don't really have the luxury of time. I know the reasons for these trials, but I'd take the risk if I could try something that could help me, even a tiny bit. :-( I feel like I am always grasping at straws. :-( Blessed Be, Meg ( <http://www.myspace.com/sexytear> http://www.myspace.com/sexytear) ( <http://blog.myspace.com/sexytear> http://blog.myspace.com/sexytear) _____ From: [mailto: ] On Behalf Of Sent: Tuesday, May 30, 2006 2:09 PM Subject: Re: Recent Article Interesting abstract - re. next generation HDAC inhibitor drug - Benzamide M344 - ...per below, initial indications 7-fold increase in full length SMN protein production (VPA & others were 3 or 4 fold I think)...more reasons to be optimistic about the future of SMA therapeutic treatments...Mitch Hum Genet. 2006 May 25; [Epub ahead of print] Related Articles, Links The benzamide M344, a novel histone deacetylase inhibitor, significantly increases SMN2 RNA/protein levels in spinal muscular atrophy cells. Riessland M, Brichta L, Hahnen E, Wirth B. Institute of Human Genetics, Institute of Genetics, and Center for Molecular Medicine Cologne, University of Cologne, Kerpener Str. 34, 50931, Cologne, Germany, brunhilde.wirth@.... Proximal spinal muscular atrophy (SMA) is a common autosomal recessively inherited neuromuscular disorder causing infant death in half of all patients. Homozygous loss of the survival motor neuron 1 (SMN1) gene causes SMA, whereas the number of the SMN2 copy genes modulates the severity of the disease. Due to a silent mutation within an exonic splicing enhancer, SMN2 mainly produces alternatively spliced transcripts lacking exon 7 and only approximately 10% of a full-length protein identical to SMN1. However, SMN2 represents a promising target for an SMA therapy. The correct splicing of SMN2 can be efficiently restored by over-expression of the splicing factor Htra2-beta1 as well as by exogenous factors like drugs that inhibit histone deacetylases (HDACs). Here we show that the novel benzamide M344, an HDAC inhibitor, up-regulates SMN2 protein expression in fibroblast cells derived from SMA patients up to 7-fold after 64 h of treatment. Moreover, M344 significantly raises the total number of gems/nucleus as well as the number of nuclei that contain gems. This is the strongest in vitro effect of a drug on the SMN protein level reported so far. The reversion of Delta7-SMN2 into FL-SMN2 transcripts as demonstrated by quantitative RT-PCR is most likely facilitated by elevated levels of Htra2-beta1. Investigations of the cytotoxicity of M344 using an MTT assay revealed toxic cell effects only at very high concentrations. In conclusion, M344 can be considered as highly potent HDAC inhibitor which is active at low doses and therefore represents a promising candidate for a causal therapy of SMA. PMID: 16724231 [PubMed - as supplied by publisher __________________________________________________ Quote Link to comment Share on other sites More sharing options...
Guest guest Posted May 30, 2006 Report Share Posted May 30, 2006 There's limited info on the web, but it looks like it's a brand new compound that hasn't been tested on humans. So while the results look promising, it will have to go through a bunch of pre-clinical testing and several clinical trials before it's available for real. There have been so many of these compounds shown to increase SMN levels in the lab - I agree it's very frustrating that none of them has made it to the real world yet. I can't help wondering if it wouldn't be better to choose a couple of these compounds and focus on getting them into the clinic, rather than finding new ones every few months. Leaving aside valproic acid, which wasn't designed for SMA and seems to be effective only in some lucky people, the closest SMA treatment to approval seems to be the Trophos drug in France, but even that is several years away. Tokyo 2006/5/31, Meg W. <pink-tulip@...>: > > Is it possible to get that drug now? These trials and waiting for results > really get to me. We, the people who are adults living with SMA, don't > really have the luxury of time. I know the reasons for these trials, but > I'd take the risk if I could try something that could help me, even a tiny > bit. :-( > > > > I feel like I am always grasping at straws. :-( > > > > Blessed Be, > > Meg > > ( <http://www.myspace.com/sexytear> > http://www.myspace.com/sexytear) > > ( <http://blog.myspace.com/sexytear> > http://blog.myspace.com/sexytear) > > _____ > > From: [mailto: ] On > Behalf Of > Sent: Tuesday, May 30, 2006 2:09 PM > > Subject: Re: Recent Article > > > > > Interesting abstract - re. next generation HDAC > inhibitor drug - Benzamide M344 - ...per below, > initial indications 7-fold increase in full length SMN > protein production (VPA & others were 3 or 4 fold I > think)...more reasons to be optimistic about the > future of SMA therapeutic treatments...Mitch > > > Hum Genet. 2006 May 25; [Epub ahead of print] Related > Articles, Links > > > The benzamide M344, a novel histone deacetylase > inhibitor, significantly increases SMN2 RNA/protein > levels in spinal muscular atrophy cells. > > Riessland M, Brichta L, Hahnen E, Wirth B. > > Institute of Human Genetics, Institute of Genetics, > and Center for Molecular Medicine Cologne, University > of Cologne, Kerpener Str. 34, 50931, Cologne, Germany, > brunhilde.wirth@.... > > Proximal spinal muscular atrophy (SMA) is a common > autosomal recessively inherited neuromuscular disorder > causing infant death in half of all patients. > Homozygous loss of the survival motor neuron 1 (SMN1) > gene causes SMA, whereas the number of the SMN2 copy > genes modulates the severity of the disease. Due to a > silent mutation within an exonic splicing enhancer, > SMN2 mainly produces alternatively spliced transcripts > lacking exon 7 and only approximately 10% of a > full-length protein identical to SMN1. However, SMN2 > represents a promising target for an SMA therapy. The > correct splicing of SMN2 can be efficiently restored > by over-expression of the splicing factor Htra2-beta1 > as well as by exogenous factors like drugs that > inhibit histone deacetylases (HDACs). Here we show > that the novel benzamide M344, an HDAC inhibitor, > up-regulates SMN2 protein expression in fibroblast > cells derived from SMA patients up to 7-fold after 64 > h of treatment. Moreover, M344 significantly raises > the total number of gems/nucleus as well as the number > of nuclei that contain gems. This is the strongest in > vitro effect of a drug on the SMN protein level > reported so far. The reversion of Delta7-SMN2 into > FL-SMN2 transcripts as demonstrated by quantitative > RT-PCR is most likely facilitated by elevated levels > of Htra2-beta1. Investigations of the cytotoxicity of > M344 using an MTT assay revealed toxic cell effects > only at very high concentrations. In conclusion, M344 > can be considered as highly potent HDAC inhibitor > which is active at low doses and therefore represents > a promising candidate for a causal therapy of SMA. > > PMID: 16724231 [PubMed - as supplied by publisher > Quote Link to comment Share on other sites More sharing options...
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