CHICAGO (Reuters) – U.S. scientists have created the first human model for studying a devastating nerve disease, which allows them to watch how the disease develops and could help researchers find a way to treat it.

Using skin cells from a child with spinal muscular atrophy, a genetic disease that attacks motor neurons in the spinal cord, researchers grew batches of nerve cells with the same genetic defects. The finding allowed scientists to watch the nerve cells die off.

“Now we can start from the beginning of development and replay the disease process in the lab dish,” Clive Svendsen of the University of Wisconsin-Madison said in a telephone interview.
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Other articles about this breakthrough:

• Patient-Derived Induced Stem Cells Retain Disease Traits
• Stem cells give scientists a window on diseases
• Scientists find potent new weapon to fight spinal muscular atrophy (The Times)
• Gene disease ‘recreated in lab’ (BBC)

Spinal Muscular Atrophy (SMA) is the most common genetic cause of infant mortality. SMA is caused by loss of functional Survival Motor Neuron 1 (SMN1), resulting in death of spinal motor neurons. Current therapeutic research focuses upon modulating the expression of a partially functioning copy gene, SMN2, which is retained in SMA patients. However, a treatment strategy that improves the SMA phenotype by slowing or reversing the skeletal muscle atrophy may also be beneficial. Myostatin, a member of the TGF-β super-family, is a potent negative regulator of skeletal muscle mass. Follistatin is a natural antagonist of myostatin and over-expression of follistatin in mouse muscle leads to profound increases in skeletal muscle mass. To determine whether enhanced muscle mass impacts SMA, we administered recombinant follistatin to a SMA mouse model. Treated animals exhibited increased mass in several muscle groups, elevation in the number and cross-sectional area of ventral horn cells, gross motor function improvement, and mean lifespan extension by 30%, by preventing some of the early deaths, as compared to control animals. SMN protein levels in spinal cord and muscle were unchanged in follistatin-treated SMA mice, suggesting that follistatin exerts its effect in an SMN-independent manner. Reversing muscle atrophy associated with SMA may represent an unexploited therapeutic target for the treatment of SMA.
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Spinal muscular atrophy, a neurodegenerative disorder that causes the weakening of muscles, is the leading cause of infant death and occurs in 1 in 6,000 live births. While trans-splicing (a form of molecular therapy) has had impressive results as a treatment for spinal muscular atrophy in cell-based models of disease, scientists have been unable to translate the therapy to the human body. A University of Missouri researcher has developed a strategy that will enhance trans-splicing activity and bring it closer to being used in the clinical setting.
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Objectives: Spinal muscular atrophy SMA is an autosomal recessive disorder characterized by loss of lower motor neurons during early or postnatal development. Severity is variable and is inversely related to the levels of survival of motor neurons SMN protein. The aim of this study was to produce a two-site ELISA capable of measuring both the low, basal levels of SMN protein in cell cultures from patients with severe SMA and small increases in these levels after treatment of cells with drugs.

Methods: A monoclonal antibody against recombinant SMN, MANSMA1, was selected for capture of SMN onto microtiter plates. A selected rabbit antiserum against refolded recombinant SMN was used for detection of the captured SMN.

Results: The ratio of SMN levels in control fibroblasts to levels in SMA fibroblasts was greater than 3.0, consistent with Western blot data. The limit of detection was 0.13 ng/mL and SMN could be measured in human NT-2 neuronal precursor cells grown in 96-well culture plates 3 x 104 cells per well. Increases in SMN levels of 50% were demonstrable by ELISA after 24 hours treatment of 105 SMA fibroblasts with valproate or phenylbutyrate.

Conclusion: A rapid and specific two-site, 96-well ELISA assay, available in kit format, can now quantify the effects of drugs on survival of motor neurons protein levels in cell cultures.

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In Spinal Muscular Atrophy, the survival motor neuron 1 gene SMN1 is deleted or inactivated. The nearly identical SMN2 gene has a silent mutation that impairs the utilisation of exon 7 and the production of functional protein. It has been hypothesised that therapies boosting SMN2 exon 7 inclusion might prevent or cure SMA. Exon 7 inclusion can be stimulated in cell culture by oligonucleotides or intracellularly expressed RNAs, but evidence for an in vivo improvement of SMA symptoms is lacking. Here we unambiguously confirm the above hypothesis by showing that a bifunctional U7 snRNA that stimulates exon 7 inclusion, when introduced by germ-line transgenesis, can efficiently complement the most severe mouse SMA model. These results are significant for the development of a somatic SMA therapy, but may also provide new means to study pathophysiological aspects of this devastating disease.

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Biologists at Bern University have made promising inroads toward treating spinal muscular atrophy, one of the leading genetic causes of early childhood death.

One out of 6,000 newborns is affected by the disease, which attacks nerve cells in the spinal cord responsible for voluntary movement. Children suffering from the disease have two missing or malfunctioning genes that are needed for the production of a critical protein for healthy muscles.

Cellular biologist Daniel Schümperli and his team have found ways to correct the problem by injecting cells with a specially developed gene, which helps synthesise the missing proteins. The scientists were able to see significant improvements in mice with even the most severe cases of spinal muscular atrophy.

"This new study shows for the first time that the methods lead to a notable reduction in disease symptoms," Schümperli said in a press release on Friday. The results have been published in the journal Human Molecular Genetics.

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FSMA, Invitrogen Corporation, and deCODE Chemistry announced today they have identified a protein that is a potential molecular target for the treatment of Spinal Muscular Atrophy (SMA).  In its most severe form, SMA often leads to death in infancy, and there is currently no treatment or cure.  Research published today in the journal ACS Chemical Biology of the American Chemical Society, entitled “DcpS as a Therapeutic Target for Spinal Muscular Atrophy,” details the identification and characterization of a protein that offers a novel biological mechanism for designing new SMA therapeutics.

Previously, researchers at deCODE, with funding from Families of SMA, had developed a class of compounds called C-5 substituted quinazolines, which increased expression of SMN protein, potentially giving clinical investigators a new class of compounds to utilize for the treatment of SMA.  However, the mechanism behind this increase in SMN production was unknown.

“While the identification of compounds that increase SMN expression represents significant hope to patients with SMA, we still did not understand the mode of action of these compounds in SMA,” noted Jill Jarecki, Ph.D., Research Director at Families of SMA. “The results outlined in the paper represent a new understanding of the physiological mechanisms that can increase SMN expression and will allow us to move forward in advancing potential treatments for SMA.  This discovery gets to the level of really understanding how SMN deficiency can be corrected in the cells of the body, which in turn will open up many new ways of developing therapies.”

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Assay Designs and the Spinal Muscular Atrophy Foundation (SMAF) are very pleased to announce a collaborative agreement for development of reagents and assays for SMN (Survival Motor Neuron) protein to expedite drug discovery and development efforts for spinal muscular atrophy (SMA), the leading genetic cause of mortality in infants and toddlers. “Assay Designs is excited and proud to have been selected by the SMA Foundation, and to help enable better understanding and ultimately improved treatment for this debilitating illness,” commented Dan Calvo, President and CEO of Assay Designs. Providing a reliable and widely-available ELISA kit for measuring SMN protein levels will greatly simplify and accelerate the process of assessing the efficacy of potential drugs in clinical trials, which is key to the successful development of new therapeutics for this devastating disease. “We are pleased to bring results from the research sector out for general use in the community,” states Loren Eng, president of the SMA Foundation.

Simple, everyday movements require the coordination of dozens of muscles, guided by the activity of hundreds of motor neurons. Now, researchers have revealed an important step in the process that guides the early development of neurons themselves, as they establish the precise connections between the spinal cord and muscles. This knowledge will help scientists search for drugs to treat diseases that destroy motor neurons, such as amyotrophic lateral sclerosis, or Lou Gehrig's disease.

As a vertebrate organism develops, the long, outstretched processes of motor neurons wend their way from the spinal column to wire up every muscle in the body. In mammals, many hundreds of different types of motor neurons are needed to control the variety of muscle types used to coordinate movement. The highly specialized motor neurons that innervate muscles in the arms, legs, hands, and feet are the most recent of these to evolve. As an animal develops, these neurons become increasingly specialized – first establishing themselves as motor neurons, then taking on the characteristics needed to control a limb, then preparing to target a specific muscle. Proper function depends on each of these neurons finding its way from the spinal cord to the group of muscle cells that it is equipped to control.
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By JEAN ENERSEN / KING 5 News

Spinal cord injuries have long baffled doctors. Now the Allen Institute for Brain Science is doing for spinal research what they did for brain science – providing the first comprehensive road map of a mouse's spine.

"It's a groundbreaking project that tells us where each gene in the genome is turned on in cells in the spinal cord," Dr. Allan Jones, Allen Institute's Chief Scientific Officer, said in a news conference Thursday. "This is very important because the genes ultimately contribute to the specific biochemistry of a particular cell."

Jones says because mice share many of the same genes with humans, the implications are far-reaching.

"Researchers working on things like spinal muscular atrophy, degenerative disease like MS and Lou Gerhig's disease or ALS , also people who suffer from spinal cord injuries," he said.

The first 2,000 genes are available online now, with the full map of 20,000 genes to be completed by the end of the year. All the information is free to scientists and the public.

"It's sort of  a virtual microscope that scientists can come and zoom in," said Jones. "It's like having the microscope slide right there in front of them."

"The comprehensive map of the genes of the spinal cord will be an incredible resource for scientists and researchers studying how the spinal cord is altered in disease or an injury, and more importantly it's going to give hope to really millions of Americans who suffer from spinal cord diseases and disorders," Sen. Patty Murray said at the news conference.

Said each day, 1,000 scientists have been accessing the Allen Brain Atlas Project, which went live in December of 2004 and was completed in 2006.

"Researchers have been using this to support all aspects of brain research," said Jones. "Just some examples: Alzheimer's, autism, bipolar, Down syndrome, Fragile X mental retardation, epilepsy, alcoholism, obesity, Parkinson's disease, sleep, hearing, memory, and more."

In December, Marine Corporal Jerold Mason was paralyzed in a car crash. These days he's grateful for the small things, like being able to listen to his I-Pod.

"It like takes you away from the stress. I will always use music to do that," he said. Mason can now control his I-Pod with a straw. This one small step is inspiring him. "Allows me to think of times when I did have the use of my arms, my legs and you know it makes me want to push harder," he said.

Thanks to the spinal cord map, researchers will be able to push harder, as well.

"It's all undiscovered new stuff. So they're a bit like a kid in a candy store in terms of the new data in the excitement of looking at it," said Jones.

Microsoft co-founder Paul Allen started the mapping project with $100 million in seed money. It's now grown to include other private, as well as public, funding.
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By Karin Kloosterman, Israel21c
The mere mention of a scorpion sends shivers up the spine—but an Israeli company, Scorpion Surgical Technologies, has created a new device that could give scorpions some good PR for a change.

The company has developed a bone attachment system that circumvents the previous limitations of today's spinal implant operations, giving patients improved spinal motion and surgeries that could last a lifetime.
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Researchers from the University of Pennsylvania School of Medicine discovered that the effect of a protein deficiency, which is the basis of the neuromuscular disease spinal muscular atrophy (SMA), is not restricted to motor nerve cells, suggesting that SMA is a more general disorder. This new insight will allow for better understanding of how this complex disease arises. Gideon Dreyfuss, PhD, the Isaac Norris Professor of Biochemistry and Biophysics and Investigator, Howard Hughes Medical Institute and colleagues, report their findings in last week’s issue of Cell.
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Gabriela E. Oprea, Sandra Kröber, Michelle L. McWhorter, Wilfried Rossoll, Stefan Müller, Michael Krawczak, Gary J. Bassell, Christine E. Beattie, Brunhilde Wirth

Homozygous deletion of the survival motor neuron 1 gene (SMN1) causes spinal muscular atrophy (SMA), the most frequent genetic cause of early childhood lethality. In rare instances, however, individuals are asymptomatic despite carrying the same SMN1 mutations as their affected siblings, thereby suggesting the influence of modifier genes. We discovered that unaffected SMN1-deleted females exhibit significantly higher expression of plastin 3 (PLS3) than their SMA-affected counterparts. We demonstrated that PLS3 is important for axonogenesis through increasing the F-actin level. Overexpression of PLS3 rescued the axon length and outgrowth defects associated with SMN down-regulation in motor neurons of SMA mouse embryos and in zebrafish. Our study suggests that defects in axonogenesis are the major cause of SMA, thereby opening new therapeutic options for SMA and similar neuromuscular diseases.
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Gavrilina TO, McGovern VL, Workman E, Crawford TO, Gogliotti RG, Didonato CJ, Monani UR, Morris GE, Burghes HM, Department of Molecular and Cellular Biochemistry, The Ohio State University, USA

Spinal muscular atrophy is caused by loss of the SMN1 gene and retention of the SMN2 gene. The copy number of SMN2 affects the amount of SMN protein produced and the severity of the SMA phenotype. While loss of mouse Smn is embryonic lethal, two copies of SMN2 prevents this embryonic lethality resulting in a mouse with severe SMA that dies 5 days after birth. Here we show that expression of full-length SMN under the Prion promoter (PrP) rescues severe SMA mice. The prion promoter results in high levels of SMN in neurons at embryonic day 15. Mice homozygous for PrP-SMN with two copies of SMN2 and lacking mouse Smn survive for an average of 210 days and lumbar motor neuron root counts in these mice were normal. Expression of SMN solely in skeletal muscle using the human skeletal actin (HSA) promoter resulted in no improvement of the SMA phenotype or extension of survival. One HSA line displaying nerve expression of SMN did affect the SMA phenotype with mice living for an average of 160 days. Thus, we conclude that expression of full-length SMN in neurons can correct the severe SMA phenotype in mice. Furthermore, a small increase of SMN in neurons has a substantial impact on survival of SMA mice while high SMN levels in mature skeletal muscle alone has no impact.
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The Spinal Muscular Atrophy Foundation and BG Medicine today announced a collaboration to discover plasma biomarkers of drug efficacy for spinal muscular atrophy (SMA), the leading genetic cause of mortality in infants and toddlers. This project seeks to discover a clinically-useful molecular biomarker, which can then be used to monitor the efficacy of potential drugs in clinical trials.

“We are pleased to be launching this important step in drug development efforts for SMA,” said Karen Chen, Director, Pre-Clinical Research for the Foundation. “The identification of relevant biomarkers is key to the successful development of new therapeutics for this devastating disease. The unbiased discovery approach taken in this project will add substantially to our understanding of disease and drug effects.”
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Brief summaries of presentations by 16 leading SMA researchers at the 2007 Fight SMA Conference are available here.

Leading European researchers and clinicians have joined forces in a newly launched Network of Excellence (NoE) on finding new treatments for rare neuromuscular diseases (NMD), such as muscular dystrophies and spinal muscular atrophy.

Dubbed TREAT-NMD (Translational research in Europe – assessment and treatment of neuromuscular), the five-year network is the first of its kind in Europe, bringing together a total of 21 partner organisations from 11 countries. They include charities and companies that will work alongside doctors and researchers in the field.
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Lexicon Genetics Incorporated announced today that its research program to identify targets that may be important in the development of drugs to prevent or treat spinal muscular atrophy (SMA) has been extended for an additional year by the United States Army Medical Research & Materiel Command (USAMRMC).  SMA is a neurodegenerative disorder and the leading genetic cause of death in early childhood. 

Lexicon will receive $2.5 million in funding for the one-year extended term of the grant.  The research program was initiated under a $2.0 million award to Lexicon.  Lexicon has an agreement with the SMA Foundation for the potential development of drugs based on discoveries resulting from this program.
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During embryonic development, nerve cells hesitantly extend tentacle-like protrusions called axons that sniff their way through a labyrinth of attractive and repulsive chemical cues that guide them to their target.

While several recent studies discovered molecules that repel motor neuron axons from incorrect targets in the limb, scientists at the Salk Institute for Biological Studies have identified a molecule, known as FGF, that actively lures growing axons closer to the right destination. Their findings appear in the June 15 issue of Neuron.

“The most important aspect of our finding is not necessarily that we finally nailed the growth factor FGF as the molecule that guides a specific subgroup of motor neurons to connect to the muscles that line our spine and neck,” says senior author Samuel Pfaff, Ph.D., a professor in the Gene Expression Laboratory, “but that piece by piece, we are uncovering general principles that ensure that the developing nervous system establishes proper neuronal connections.”
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Lexicon Genetics Incorporated announced today that it was awarded a grant from the United States Army Medical Research & Materiel Command (USAMRMC) for the identification of targets that may be important in the development of drugs to prevent or treat spinal muscular atrophy (SMA), a neurodegenerative disorder and the leading genetic cause of death in early childhood.  Lexicon will receive $2.0 million in funding for the one-year initial term of the grant.

SMA is characterized by a mutation in the SMN1 gene that leads to neurodegeneration.  Under the grant, Lexicon will utilize its proprietary gene knockout technology to identify genes that, when knocked out, lead to increased levels of mouse Smn protein.  Genes that regulate Smn protein in mice may be involved in the regulation of SMN2 protein in humans.  Identification of these genes may enable the development of drugs designed to increase levels of human SMN2 protein to offset the absence of human SMN1 protein and prevent or treat SMA.  Lexicon will study approximately 750 pharmaceutically tractable genes in the research program.  Lexicon has also entered into an agreement with the SMA Foundation for the potential development of drugs based on discoveries resulting from the program.
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