recent article

[Guest guest]

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

__________________________________________________

[Guest guest]

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

__________________________________________________

[Guest guest]

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

>