Guest guest Posted August 3, 2006 Report Posted August 3, 2006 Hey all - Firt of all, hope yer all having yerselves fine days today...now, I found a good article just posted on the MDA website - & thought it might be of some interest. As an FYI, in case ya didn't know, DNA codes RNA which more or less then translates the genetic instructions into Proteins. Article below describes how researchers have been able to turn off " poisonous RNA " in Mice with a mouse-form of MMD (myotonic muscular dystrophy) from producing a particular protein - which in most cases reversed all symptoms of the MMD - this symptom 'reversal' included skeletal and heart muscle repairing themselves once the poisonous RNA was switched 'off.' Interestingly most of all (at least to me) - was the researchers comments at the very end of the article: “You might be surprised at how fast targeting the RNA will progress.” Targeting RNA coded by the genetic information of the SMN2 gene - by adding very small amounts of genetic instructions - one which would remove the stop codon instuction in Exon 7 (which is due to a single nucleotide) to allow Exon 7 & 8 to be included in the protein production - this would result in full length protein being produced versus SMN Delta 7 Protein - if this could be accomplished, the root cause of SMA (lack of sufficient full lenght SMN protein) could be addressed fully. Results noted in article below have to be extremely encouraging for those with MMD - human trials could be fairly close based on the success described. Also quite encouraging for folks with any genetic disease or condition in which RNA interference is a possible therapy strategy ( & SMA is definitely in that category)...Mitch Turning Off Toxic RNA Reverses MMD in Mice A group of researchers led by Mani Mahadevan, an MDA grantee and associate professor of pathology at the University of Virginia in Charlottesville, has announced that virtually all the effects of type 1 myotonic muscular dystrophy (MMD), at least in mice, can be reversed solely by targeting the toxic RNA associated with this disease. Mahadevan and colleagues published their findings online July 30 in Nature Genetics. “Fundamentally,” Mahadevan said, “it seems to me, if you have a poison, such as the toxic RNA seen in MMD patients, causing various defects, it’s much simpler in principle to get rid of the poison than to tackle its various effects individually. In the end, you have to tackle the underlying problem.” To see if this was possible, Mahadevan and colleagues created a new type of MMD mouse model, with extra copies of so-called DNA CTG repeats. They also integrated an “on switch” into the DNA, which they could activate by giving the mice doxycycline, an antibiotic, in their drinking water. When the activation switch was turned on, cells in the mice began the normal process of transcribing the DNA CTG repeats into similar RNA repeats but, because of the extra copies, they made about 10 to 15 times the normal amount of RNA. Within a few weeks, the mice developed all the hallmarks of type 1 MMD: myotonia, an inability to relax muscles; a heart rhythm abnormality known as a conduction block; and fetal, rather than adult, forms of several proteins. When the doxycycline was stopped, the DNA was inactivated, and the mice stopped transcribing it into RNA. The mice, surprising the investigators, returned to normal in all respects, except in cases where the heart was very severely affected. “Tissues that you think are irreversibly damaged, like skeletal muscle or heart, we could actually fix,” Mahadevan said. “I was especially surprised that the heart could repair itself, as I had never seen that before.” Unlike other mouse models of MMD, and unlike humans with MMD, these mice didn’t have clumps of extra RNA and proteins in their cell nuclei, a phenomenon that many investigators see as a key cause of disease manifestations. Nevertheless, they developed an MMD-like condition. Mahadevan says his mice had RNA pieces that were both necessary and sufficient to cause MMD -- presumably just because there were more of them than normal -- even though they didn’t form clumps. “If you take away the poisonous RNA the way we do it, by shutting off the gene, no RNA gets made anymore, the muscles get better, and the heart gets better,” Mahadevan said. On July 24, a group including MDA grantee Maurice Swanson at the University of Florida published different findings about type 1 MMD online in the Proceedings of the National Academy of Sciences. The Florida group showed that adding genes for a protein known as MBNL1, which is bound up with toxic RNA in clumps in a different MMD mouse model and in humans with the disease, reversed myotonia and restored four muscle proteins to normal. Mahadevan said that, although this approach might be more feasible for now, it’s correcting only some of the problems caused by the toxic RNA, rather than getting at the root cause of MMD, the RNA itself. As for how toxic RNA can be targeted in patients, who can’t be engineered with DNA on-off switches, he said, “You might be surprised at how fast targeting the RNA will progress.” __________________________________________________ Quote
Guest guest Posted August 4, 2006 Report Posted August 4, 2006 & all: I agree and am with youu 100% - first step is to restore SMN protein levels to normal or near normal by any of the methods you mentioned - with the least amount of possible side effects. The 2nd Step is to replenish lost MN's. Could partially be accomplished through step 1 - since NO doc or researcher actually KNOWS when & how fast MN's die off due to lack of sufficient SMNfl protein - and perhaps replenishing flSMN levels will indeed result in some recusitated MN's and resulting regained lost strength or function. Though, for sure, to see real reversal of significant SMA symptoms will require some sort of Stem Cell Therapy (which as we all know has been accomplished to certain levels of success already in lab animals). BUT, STEP 1 is Huge - stopping any additional progression of symptoms caused by SMA would be fantastic as a start. And without Step 1, there can be no second step. By the way - August is SMA Awareness month - or so it has been dubbed - I just sent out an email to about 200 people and asked them to send it along to 10 more people. Raising awareness of SMA (so that people have at least heard of SMA - which I'd surmise 99% of at least the US pop. has not) - will go a long way to SMA realizing comparable research dollars from both private and public sources. On a different matter - we'll be celebrating two birthdays this month. My daughter is turns 4 on Monday - so Princess birthday party tomorrow! Bryce will be 6 on August 31 - kindergarten start in only a few weeks! Have a nice weekend one & all. Mitch --- Senior <jsenior@...> wrote: > Very interesting Mitch, thanks. I also like the > sound of that last > comment. It seems pretty clear that at some point > there will be a > treatment that restores SMN protein levels to normal > or near-normal > levels - maybe it'll be a " small molecule, " maybe a > next-generation > HDAC inhibitor, maybe something like this MMD > treatment. The huge > question remains whether, like in the MMD mice, such > a treatment will > result in the body repairing the damaged motor > neurons and muscles, > thus reversing SMA, or whether it will just stop > further damage. Even > if it's the former, no amount of protein will bring > back the MNs that > have already died, so a complete cure for SMA surely > depends on MN > regeneration - ie. stem cell treatment. A drug that > restored sick MNs > to health would still be an incredible breakthrough, > though. > > > > > 2006/8/4, <mongomustgolf@...>: > > Hey all - Firt of all, hope yer all having > yerselves > > fine days today...now, I found a good article > just > > posted on the MDA website - & thought it might be > of > > some interest. > > > > As an FYI, in case ya didn't know, DNA codes RNA > which > > more or less then translates the genetic > instructions > > into Proteins. Article below describes how > researchers > > have been able to turn off " poisonous RNA " in > Mice > > with a mouse-form of MMD (myotonic muscular > dystrophy) > > from producing a particular protein - which in > most > > cases reversed all symptoms of the MMD - this > symptom > > 'reversal' included skeletal and heart muscle > > repairing themselves once the poisonous RNA was > > switched 'off.' Interestingly most of all (at > least > > to me) - was the researchers comments at the very > end > > of the article: " You might be surprised at how > fast > > targeting the RNA will progress. " > > > > Targeting RNA coded by the genetic information of > the > > SMN2 gene - by adding very small amounts of > genetic > > instructions - one which would remove the stop > codon > > instuction in Exon 7 (which is due to a single > > nucleotide) to allow Exon 7 & 8 to be included in > the > > protein production - this would result in full > length > > protein being produced versus SMN Delta 7 Protein > - if > > this could be accomplished, the root cause of SMA > > (lack of sufficient full lenght SMN protein) > could be > > addressed fully. > > > > Results noted in article below have to be > extremely > > encouraging for those with MMD - human trials > could be > > fairly close based on the success described. Also > > quite encouraging for folks with any genetic > disease > > or condition in which RNA interference is a > possible > > therapy strategy ( & SMA is definitely in that > > category)...Mitch > > > > Turning Off Toxic RNA Reverses MMD in Mice > > A group of researchers led by Mani Mahadevan, an > MDA > > grantee and associate professor of pathology at > the > > University of Virginia in Charlottesville, has > > announced that virtually all the effects of type > 1 > > myotonic muscular dystrophy (MMD), at least in > mice, > > can be reversed solely by targeting the toxic RNA > > associated with this disease. Mahadevan and > colleagues > > published their findings online July 30 in Nature > > Genetics. > > > > " Fundamentally, " Mahadevan said, " it seems to me, > if > > you have a poison, such as the toxic RNA seen in > MMD > > patients, causing various defects, it's much > simpler > > in principle to get rid of the poison than to > tackle > > its various effects individually. In the end, you > have > > to tackle the underlying problem. " > > > > To see if this was possible, Mahadevan and > colleagues > > created a new type of MMD mouse model, with extra > > copies of so-called DNA CTG repeats. > > > > They also integrated an " on switch " into the DNA, > > which they could activate by giving the mice > > doxycycline, an antibiotic, in their drinking > water. > > > > When the activation switch was turned on, cells > in the > > mice began the normal process of transcribing the > DNA > > CTG repeats into similar RNA repeats but, because > of > > the extra copies, they made about 10 to 15 times > the > > normal amount of RNA. > > > > Within a few weeks, the mice developed all the > > hallmarks of type 1 MMD: myotonia, an inability > to > > relax muscles; a heart rhythm abnormality known > as a > > conduction block; and fetal, rather than adult, > forms > > of several proteins. > > > > When the doxycycline was stopped, the DNA was > > inactivated, and the mice stopped transcribing it > into > > RNA. The mice, surprising the investigators, > returned > > to normal in all respects, except in cases where > the > > heart was very severely affected. > > > > " Tissues that you think are irreversibly damaged, > like > > skeletal muscle or heart, we could actually fix, " > > Mahadevan said. " I was especially surprised that > the > > heart could repair itself, as I had never seen > that > > before. " > > > > Unlike other mouse models of MMD, and unlike > humans > > with MMD, these mice didn't have clumps of extra > RNA > > and proteins in their cell nuclei, a phenomenon > that > > many investigators see as a key cause of disease > > manifestations. Nevertheless, they developed an > > MMD-like condition. > > > > Mahadevan says his mice had RNA pieces that were > both > > necessary and sufficient to cause MMD -- > presumably > > just because there were more of them than normal > -- > > even though they didn't form clumps. > > > > " If you take away the poisonous RNA the way we do > it, > > by shutting off the gene, no RNA gets made > anymore, > > the muscles get better, and the heart gets > better, " > > Mahadevan said. > > > > On July 24, a group including MDA grantee Maurice > > Swanson at the University of Florida published > > different findings about type 1 MMD online in the > > Proceedings of the National Academy of Sciences. > > > > The Florida group showed that adding genes for a > > protein known as MBNL1, which is bound up with > toxic > > RNA in clumps in a different MMD mouse model and > in > === message truncated === __________________________________________________ Quote
Guest guest Posted August 7, 2006 Report Posted August 7, 2006 Is there anyway to contact this researcher and see if we can steer him towards SMA research ? > > > Very interesting Mitch, thanks. I also like the > > sound of that last > > comment. It seems pretty clear that at some point > > there will be a > > treatment that restores SMN protein levels to normal > > or near-normal > > levels - maybe it'll be a " small molecule, " maybe a > > next-generation > > HDAC inhibitor, maybe something like this MMD > > treatment. The huge > > question remains whether, like in the MMD mice, such > > a treatment will > > result in the body repairing the damaged motor > > neurons and muscles, > > thus reversing SMA, or whether it will just stop > > further damage. Even > > if it's the former, no amount of protein will bring > > back the MNs that > > have already died, so a complete cure for SMA surely > > depends on MN > > regeneration - ie. stem cell treatment. A drug that > > restored sick MNs > > to health would still be an incredible breakthrough, > > though. > > > > > > > > > > 2006/8/4, <mongomustgolf@...>: > > > Hey all - Firt of all, hope yer all having > > yerselves > > > fine days today...now, I found a good article > > just > > > posted on the MDA website - & thought it might be > > of > > > some interest. > > > > > > As an FYI, in case ya didn't know, DNA codes RNA > > which > > > more or less then translates the genetic > > instructions > > > into Proteins. Article below describes how > > researchers > > > have been able to turn off " poisonous RNA " in > > Mice > > > with a mouse-form of MMD (myotonic muscular > > dystrophy) > > > from producing a particular protein - which in > > most > > > cases reversed all symptoms of the MMD - this > > symptom > > > 'reversal' included skeletal and heart muscle > > > repairing themselves once the poisonous RNA was > > > switched 'off.' Interestingly most of all (at > > least > > > to me) - was the researchers comments at the very > > end > > > of the article: " You might be surprised at how > > fast > > > targeting the RNA will progress. " > > > > > > Targeting RNA coded by the genetic information of > > the > > > SMN2 gene - by adding very small amounts of > > genetic > > > instructions - one which would remove the stop > > codon > > > instuction in Exon 7 (which is due to a single > > > nucleotide) to allow Exon 7 & 8 to be included in > > the > > > protein production - this would result in full > > length > > > protein being produced versus SMN Delta 7 Protein > > - if > > > this could be accomplished, the root cause of SMA > > > (lack of sufficient full lenght SMN protein) > > could be > > > addressed fully. > > > > > > Results noted in article below have to be > > extremely > > > encouraging for those with MMD - human trials > > could be > > > fairly close based on the success described. Also > > > quite encouraging for folks with any genetic > > disease > > > or condition in which RNA interference is a > > possible > > > therapy strategy ( & SMA is definitely in that > > > category)...Mitch > > > > > > Turning Off Toxic RNA Reverses MMD in Mice > > > A group of researchers led by Mani Mahadevan, an > > MDA > > > grantee and associate professor of pathology at > > the > > > University of Virginia in Charlottesville, has > > > announced that virtually all the effects of type > > 1 > > > myotonic muscular dystrophy (MMD), at least in > > mice, > > > can be reversed solely by targeting the toxic RNA > > > associated with this disease. Mahadevan and > > colleagues > > > published their findings online July 30 in Nature > > > Genetics. > > > > > > " Fundamentally, " Mahadevan said, " it seems to me, > > if > > > you have a poison, such as the toxic RNA seen in > > MMD > > > patients, causing various defects, it's much > > simpler > > > in principle to get rid of the poison than to > > tackle > > > its various effects individually. In the end, you > > have > > > to tackle the underlying problem. " > > > > > > To see if this was possible, Mahadevan and > > colleagues > > > created a new type of MMD mouse model, with extra > > > copies of so-called DNA CTG repeats. > > > > > > They also integrated an " on switch " into the DNA, > > > which they could activate by giving the mice > > > doxycycline, an antibiotic, in their drinking > > water. > > > > > > When the activation switch was turned on, cells > > in the > > > mice began the normal process of transcribing the > > DNA > > > CTG repeats into similar RNA repeats but, because > > of > > > the extra copies, they made about 10 to 15 times > > the > > > normal amount of RNA. > > > > > > Within a few weeks, the mice developed all the > > > hallmarks of type 1 MMD: myotonia, an inability > > to > > > relax muscles; a heart rhythm abnormality known > > as a > > > conduction block; and fetal, rather than adult, > > forms > > > of several proteins. > > > > > > When the doxycycline was stopped, the DNA was > > > inactivated, and the mice stopped transcribing it > > into > > > RNA. The mice, surprising the investigators, > > returned > > > to normal in all respects, except in cases where > > the > > > heart was very severely affected. > > > > > > " Tissues that you think are irreversibly damaged, > > like > > > skeletal muscle or heart, we could actually fix, " > > > Mahadevan said. " I was especially surprised that > > the > > > heart could repair itself, as I had never seen > > that > > > before. " > > > > > > Unlike other mouse models of MMD, and unlike > > humans > > > with MMD, these mice didn't have clumps of extra > > RNA > > > and proteins in their cell nuclei, a phenomenon > > that > > > many investigators see as a key cause of disease > > > manifestations. Nevertheless, they developed an > > > MMD-like condition. > > > > > > Mahadevan says his mice had RNA pieces that were > > both > > > necessary and sufficient to cause MMD -- > > presumably > > > just because there were more of them than normal > > -- > > > even though they didn't form clumps. > > > > > > " If you take away the poisonous RNA the way we do > > it, > > > by shutting off the gene, no RNA gets made > > anymore, > > > the muscles get better, and the heart gets > > better, " > > > Mahadevan said. > > > > > > On July 24, a group including MDA grantee Maurice > > > Swanson at the University of Florida published > > > different findings about type 1 MMD online in the > > > Proceedings of the National Academy of Sciences. > > > > > > The Florida group showed that adding genes for a > > > protein known as MBNL1, which is bound up with > > toxic > > > RNA in clumps in a different MMD mouse model and > > in > > > === message truncated === > > > __________________________________________________ > Quote
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