Historically, it has been difficult to attract pharmaceutical companies to research projects on orphan diseases like Spinal Musular Atrophy because the small patient populations have small profit potential. Consequently, Families of SMA tries to reduce the risks for industrial partners and build incentives for them to work on SMA by providing funding, research tools, and scientific expertise. This strategy effectively lowers the barriers to embarking in SMA drug discovery. Our industry partners are then able to gather the needed preliminary data that ultimately leads to their own and the government’s financial investment in the research.
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FSMA has invested significant resources in alternative approaches that show promise to cure Spinal Muscular Atrophy rather than just treat the symptoms. In particular, we have invested $1.5 Million to develop a motor neuron replacement therapy for SMA, and we have made significant progress with our investment.

Our initial investment in stem cell research in 2000 funded efficacy studies using motor neurons from mouse stem cells. Results show that this therapy can provide benefit to rodents with motor neuron disease: a highly significant finding. In 2005, additional FSMA funding lead to the first, highly-pure therapeutic population of human motor neurons for cellular replacement therapy for SMA. This program is now progressing on the path to IND in collaboration with the biotech firm California Stem Cell, Inc. (CSC), and leading research centers at University of California-Irvine, and Johns Hopkins University. These motor neurons recently completed a series of critical animal safety studies prior to advancing into human trials for SMA.
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Collaborative research involving Rutgers scientist Mike Kiledjian may lead to a drug treatment for spinal muscular atrophy (SMA), the leading cause of hereditary infant death in the United States.

SMA interferes with development of motor neurons, resulting in muscle weakness and possible death. It occurs once in 6,000 births. In SMA-affected infants, a faulty gene stops production of an essential protein known as SMN. The protein normally promotes motor neuron survival. However, the body has another genetic system that typically acts as a backup, producing small quantities of normal protein. One in 6,000 infants are afflicted with spinal muscular atrophy.

While this backup system itself often cannot produce enough protein for long-term survival, its production can be increased twofold with the introduction of a compound known as C5-quinazoline. The latest research by Kiledjian and his colleagues focuses on this synthetic alkaloid compound. It is related to quinine – generally known as a treatment for malaria.
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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.
Read the full article

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)

Trophos SA, a clinical stage pharmaceutical company developing innovative therapeutics for indications with under-served needs in neurology and cardiology, announced today that the company is increasing the focus of its development programs on neuroprotection and cardioprotection. The Company has a novel and proprietary cholesterol-oxime based pipeline of drug candidates that enhance the function and survival of stressed cells via modulation of dysfunctional mitochondria, through interactions at the permeability transition pore (mPTP). The announcement follows the award of nearly USD 9 million in grants associated with its lead drug candidate TRO19622

Advancing programs include:

MitoTarget: a Trophos led consortium has been awarded a EUR 6 million grant to study restorative approaches for therapy of neurodegenerative diseases, notably including support for a clinical efficacy study of TRO19622 in Amyotrophic Lateral Sclerosis (ALS) patients.

TRO19622: development in Spinal Muscular Atrophy (SMA), an orphan neurodegenerative disorder, continues following successful phase Ib study in SMA patients.

The Company will continue its development programmed in SMA with TRO19622 following a phase Ib PK and tolerability study in SMA patients ranging from 6-25 years old, which demonstrated good tolerability and established the pharmacokinetic characteristics of the molecule in children. Discussions are ongoing with the EMEA regarding appropriate trial design to demonstrate efficacy and allow registration in this indication. This program has received financial support from the Association Française contre les Myopathies (AFM).

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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.

Read the original abstract.

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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Dalhousie Medical School researchers have discovered that embryonic stem cells may play a critical role in helping people with nerve damage and motor neuron diseases, such as amyotrophic lateral sclerosis (ALS), regain muscular strength.

Motor neurons reside in the spinal cord and control limb movements by enabling muscles to contract. Diseases like ALS cause them to degenerate, resulting in muscle weakness, atrophy, and eventual paralysis.

“This study builds on a series of studies in which we demonstrated that motor neurons can be generated from mouse embryonic stem cells,” says Dr. Victor Rafuse, associate professor of anatomy & neurobiology. “It’s very exciting that these neurons can be used for transplantation to prevent degeneration of muscle.”
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A novel drug that enables the production of normal proteins from mutated DNA might one day help people with a variety of genetic diseases. The drug has shown promise as a treatment for cystic fibrosis and muscular dystrophy, and it is now being tested in large, international clinical trials.

Most drugs alter the activity of proteins after they’re manufactured, but the new drug intervenes in the cellular machinery that makes the proteins in the first place. Consequently, it could be effective against diseases where completely different proteins go awry. “It’s a great breakthrough,” says Robert Singer, a biologist at the Albert Einstein Medical School, in New York, who is not involved with the company that produces the drug.

Severe genetic disorders, such as muscular dystrophy, result from mutations in genes that code for vital proteins. In some cases, the mutation is a misplaced genetic stop sign, a sequence that tells the cellular machinery to halt production before the protein is complete. The result can be a truncated, ineffective version of the protein, or none at all. The new drug, being developed by PTC Therapeutics, a startup in South Plainfield, NJ, allows the cellular machinery to essentially skip over these aberrant stop signs and produce normal molecules.

While severe genetic diseases are individually rare, mutations that prematurely truncate protein production are found in many of them–including spinal muscular atrophy, hemophilia, and retinitis pigmentosa. “Since the drug treats the underlying gene-expression problem, it is applicable to a few thousand diseases,” says Allan Jacobson, chair of the department of Molecular Genetics and Microbiology at the University of Massachusetts Medical School, in Worcester, and a PTC cofounder.
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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.”

Read full press release.

Repligen Corporation today reported publication of a preclinical study demonstrating that a novel histone deacetylase (HDAC) inhibitor improved disease symptoms in a transgenic animal model of Huntington's disease. The study, led by scientists at The Scripps Research Institute, demonstrated that oral administration of the drug candidate to the mice after the onset of symptoms slowed the progression of disease. Treated animals showed superior motor performance by multiple measures, reduced loss of body weight, reduced brain atrophy and improved overall appearance compared to untreated animals.

In addition to Huntington's disease, Repligen is evaluating this family of compounds for activity in preclinical models of other neurodegenerative diseases including spinal muscular atrophy.
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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.

The motor neuron disease Spinal Muscular Atrophy (SMA) is the second most common genetic disorder leading to death in childhood. There is currently no cure for SMA, but some clinicians and researchers consider stem cell transplantation as a potential therapeutic strategy. And now, Giacomo Comi and colleagues, at the University of Milan, Italy, have generated data using a mouse model of SMA to suggest that spinal cord neural stem cells (NSCs) might be a possible treatment for individuals with SMA.

In the study, NSCs from mice in which a green marker protein was expressed only in nerve cells known as motor neurons (the cells that are defective in SMA) were transplanted into the fluid bathing the spinal cord of mice with an SMA-like disease. The transplanted cells developed into a small number of motor neurons and the treated mice showed improved muscular function and increased lifespan, when compared with untreated mice. Further analysis indicated that the major effect of NSC transplantation was that the transplanted cells improved the survival and function of the motor neurons already in the mice, making them more like normal motor neurons (at the gene expression level). The authors therefore suggest that in the future, NSCs might be used in the development of therapeutic protocols for the treatment of SMA and other motor neuron diseases.
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A paper published in Annals of Neurology by the research group of Dr. Charlotte Sumner at Johns Hopkins University and partially funded by Families of SMA, shows for the first time sustained survival in SMA mice after using a specific drug regimen.

This regimen entailed early treatment with the histone deacetylase inhibitor trichostatin A (TSA), starting on day 2 post birth and nutritional support including infant formula by mouth and subcutaneous fluids, starting on day 8 post birth.  Average survival time was extended by 170%, while in experiments using just TSA treatment alone survival was extended by 40% and by 19% when TSA alone began later on day 5 post birth.  Nutritional support alone did not extend survival times. 

TSA is not suitable for human use, but other potent second generation HDAC inhibitors are currently being explored as possible treatments for SMA.
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After nearly a decade of setbacks and false starts, stem-cell science finally seems to be hitting its stride. Just a year after Japanese scientists first reported that they had generated stem cells by reprogramming adult skin cells — without using embryos — American researchers have managed to use that groundbreaking technique to achieve another scientific milestone. They created the first nerve cells from reprogrammed stem cells — an important demonstration of the potential power of stem-cell-based treatments to cure disease.
Read the full TIME article..

Other articles on this breakthrough:

• Coverage of ALS treatment from reprogrammed skin cells (With links to many news articles)
• Nerve cells grown from new-style stem cells (Reuters)
• Harvard-Columbia team creates neurons from ALS patient’s skin cells (Eurekalert)
• Patient’s own cells mass produced for first time in lab (Daily Telegraph)
• Skin cells could help with treatment of Alzheimer’s (Guardian)

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.
Read full Howard Hughes Medical Institute article.

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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A tiny start-up company in Irvine has a shot at becoming the first to gain federal approval to test an embryonic stem cell treatment in humans.

Two degenerative nerve diseases are the first targets for California Stem Cell Inc.’s therapies. They are ALS, or Lou Gehrig’s Disease, which kills adults, and SMA, a fatal disease affecting newborns. The company hopes to win Food and Drug Administration approval next year to begin clinical trials for both sets of patients.
Read the full article here at OC register.com.

Pane M, Staccioli S, Messina S, D’Amico A, Pelliccioni M, Mazzone ES, Cuttini M, Alfieri P, Battini R, Main M, Muntoni F, Bertini E, Villanova M, Mercuri E. Department of Paediatric Neurology, Catholic University, Rome, Italy.

The aim of this open pilot study was to establish the profile of tolerability and clinical response of salbutamol (albuterol) in a cohort of young children affected by type II spinal muscular atrophy (SMA). Twenty-three children between 30 months and 6 years of age were treated with salbutamol (2mg three times a day) for 1 year. All children were longitudinally assessed using the Hammersmith motor functional scale 6 months before treatment started (T0), at baseline (T1) and 6 and 12 months later. There was no significant change in function between T0 and T1 assessments, but the functional scores recorded after 6 and 12 months of treatment were significantly higher than those recorded at baseline (p=0.006). Our results suggest that salbutamol may be beneficial to SMA patients without producing any major side effect. Larger prospective randomized, double-blind, placebo controlled trials are needed to confirm these preliminary findings.
Read original abstract at PubMed

Families of Spinal Muscular Atrophy (FSMA) and Paratek Pharmaceuticals, Inc. today announced they have extended and significantly expanded their joint research and development collaboration to develop a drug candidate for the treatment of Spinal Muscular Atrophy (SMA), the leading genetically inherited cause of death of children under the age of two years. The collaboration is focused on optimizing and advancing into the clinic a novel small molecule within Paratek’s library derived from the tetracycline class of compounds.

The partners have agreed to extend their collaboration for a third year and to approximately triple the resources dedicated to the program, with both partners increasing their investment in the effort. The Krainer Laboratory at Cold Spring Harbor Laboratory and the Hastings Laboratory at Rosalind Franklin University of Medicine and Science are also key collaborators in the program. Read the rest of this entry »

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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Patients with Lou Gehrig’s disease face a dismal prognosis. The only approved drug, Sanofi-Aventis’s Rilutek, slows the fatal muscle-wasting disease by just a few months. Numerous experimental drugs have flopped in trials.

Can stem cells break the logjam?

That’s the hope behind a path-breaking new collaboration between California Stem Cell, a biotech company in Irvine, Calif.; the charitable ALS Association; and a small Belgian drug discovery company. The concept is to use motor neuron cells the biotech firm has generated from embryonic stem cells to hunt for new drugs to treat amyotrophic lateral sclerosis, more commonly called ALS, or Lou Gehrig’s disease.
Read the full Forbes article

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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In the neuromuscular disease called spinal muscular atrophy, or SMA, a protein deficiency caused by a single gene mutation leads to serious damage in growing nerve cells and the muscles they control.

Now, in laboratory experiments, researchers at Cold Spring Harbor Laboratory (CSHL) and Isis Pharmaceuticals have induced cells to replenish the protein by activating an existing, slightly modified copy of the mutant gene. These early results hold out hope for one day successfully treating this often-fatal disease.
Read the full press release

Two years ago, University of Delaware scientist Eric Kmiec showed up at A.I. duPont Hospital for Children in Rockland to find a use for his patented gene therapy.

He wanted to test the therapy, which basically edits a single letter code in a DNA sequence, on a disease. The match: spinal muscular atrophy.
Read the full article from the The News Journal

Families of Spinal Muscular Atrophy (FSMA); a stem cell scientist at University of California, Irvine (UCI); and California Stem Cell, Inc. (CSC) are pleased to announce a partnership to advance a potential stem cell therapy for SMA to human clinical trials. The specific set of animal studies planned, which will be conducted in accordance with FDA regulations, will assess the safety of motor neuron progenitors derived from human stem cells after transplantation.

These safety studies are the critical steps in advancing stem cell therapy into human trials for SMA. High purity human motor neuron populations for use in transplant therapies were developed by CSC and have been used successfully in proof of concept efficacy and preliminary safety studies in the laboratory of Dr. Hans Keirstead at UCI with funding from FSMA. CSC employs scalable manufacturing protocols to produce and supply the large population of clinical-grade motor neuron progenitors required for these pivotal studies and future human clinical trials.
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Researchers at the University of Delaware have discovered a novel technique—that acts like a “spell-checker” for correcting a misspelling in the DNA code—to repair the defective gene that causes spinal muscular atrophy (SMA). This hereditary neuromuscular disease is the number-one genetic killer of children under two years old. Babies born with Type 1 SMA, the most severe form of the disease, can’t walk, crawl, sit unsupported, lift their heads, or breathe normally. Fifty percent die before their second birthday.

The research is published in the Jan. 14 online edition of Experimental Cell Research. The study was supported by $477,500 in National Tobacco Settlement funds to the state of Delaware. The research grant was awarded through the Delaware Health Fund.

“Think of it like a spell-check program—we’re erasing the wrong letter in the DNA code and putting the right one in,” said Eric Kmiec, professor of biological sciences at UD.
Read the full press release

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.
Read the abstract on PubMed

Liang WC, Yuo CY, Chang JG, Chen YC, Chang YF, Wang HY, Ju YH, Chiou SS, Jong YJ, Department of Pediatrics, Kaohsiung Medical University Hospital, Taiwan

BACKGROUND: Spinal muscular atrophy (SMA) is a degenerative motor neuron disease caused by homozygous mutations of the survival motor neuron 1 (SMN1) gene. Effective treatment for SMA is unavailable at present. The aim of this study was to investigate the effect of hydroxyurea (HU) in SMA cells and patients.

MATERIALS AND METHODS: Fifteen SMA lymphoid and three fibroblast cell lines, 2 from SMA patients and 1 control, were treated with HU at different concentrations, and 33 patients (types II, III) randomized into three groups on different HU dosage, 20, 30, 40 mg/kg/day, were treated for 8 weeks and followed up for another drug-free 8 weeks. The effect of HU on SMN2 gene expression and clinical manifestations was evaluated.

RESULTS: After treatment, in vitro, full-length mRNA level and gems number increased significantly, and hnRNP A1 protein decreased. In vivo, there were slight increases in muscle strength scores at 4 weeks and full-length SMN mRNA at 8 weeks in 30 mg/kg/day subgroup.

CONCLUSIONS: Treating with HU enhanced SMN2 gene expression in SMA cells and showed slight trend towards improvement in some clinical outcome measures in SMA patients which suggests HU may be safe to use in SMA patients but larger randomized, placebo-controlled, double-blind trials are needed to further investigate its efficacy.
Read the abstract on PubMed

PTC Therapeutics, Inc. (PTC), a biopharmaceutical company focused on the discovery, development, and commercialization of small-molecule drugs targeting post-transcriptional control mechanisms, today announced an expanded research collaboration with the Spinal Muscular Atrophy (SMA) Foundation.  The collaboration builds on the existing research agreement to identify and characterize compounds that have the potential to treat SMA by increasing production of the survival motor neuron (SMN) protein, the absence of which causes SMA.  Under the terms of the expanded agreement, the SMA Foundation will provide an additional $1.6 million in funding to PTC based upon completion of certain milestones.
Read the full press release

Neuralstem Inc., the tiny Rockville biotech whose human stem cells have helped paralyzed rats walk again, is poised to launch its first trials on severe spinal cord conditions in humans.

The 11-year-old company is finally readying for trials of its patented nerve stem cell products on the first three of its possible targets: traumatic spinal cord injury; another type of paralysis often associated with stroke; and amyotrophic lateral sclerosis, known as Lou Gehrig’s disease. There are no cures for the conditions. In a study at Johns Hopkins, Neuralstem stem cells extended the life of rats with a form of ALS.
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Links to slides from the presentations at the summit can be found here.

Executive Summary
The SMA Summit on Drug Development was held on September 28th and 29th 2007 in Bethesda, MD. The event was hosted by the Patient Advisory Group (PAG) of the International Coordinating Committee for SMA clinical trials (ICC), which includes Families of SMA, Fight SMA, MDA, and the SMA Foundation. The ICC is a volunteer committee composed of stakeholders from the Spinal Muscular Atrophy (SMA) community who work together to address the opportunities and challenges associated with effectively organizing clinical trials of new treatments for SMA. The ICC consists of six working groups: the Patient Advisory Group, the Outcomes Measures Group, the Protocol Design Group, the Standard of Care Group, the Biomarkers Group, and the Registry / Database Group.

The SMA Summit on Drug Development was convened in anticipation of major drug efficacy trials for SMA in order to foster dialogue between stakeholders, to identify barriers to successful drug development, and to develop strategies to address these gaps in the pathway to regulatory approval. Attendees included representatives from the biotech and pharmaceutical industries, international advocacy groups, clinicians, and government. Participants discussed the currently available clinical infrastructure, the existing SMA therapeutic pipeline, and the regulatory requirements for evaluating new SMA treatments.
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Trophos SA, a biopharmaceutical company specializing in the discovery and development of drugs for neurological disorders, announced today that the company has begun enrolling Spinal Muscular Atrophy (SMA) patients in a Phase Ib clinical trial of its lead product, TRO19622. The clinical trial will involve 20 type 1b-3 SMA patients aged between 6 – 25 years of age and will assess the pharmacokinetics and safety of drug product after administration of single and multiple doses, once-daily, by the oral route. The study is being conducted at three centers in France. The clinical program in SMA is supported by the Association Française contre les Myopathies (AFM, www.afm-france.org), through a strategic partnership begun in 2000.

TRO19622 is representative of novel compounds identified using the proprietary neuronal cell screening platform developed at Trophos. Preclinical studies have demonstrated that these compounds promote the survival of a wide range of neurons under disease relevant stress conditions. TRO19622 has successfully completed Phase I/Ib studies in both healthy volunteers and ALS patients demonstrating the product is well tolerated, has an excellent safety profile and that once-a-day dosing achieves the predicted exposure level required for efficacy, based on preclinical models. The European Commission has granted the company an ‘Orphan Medicinal Product’ designation for TRO19622 as a treatment for SMA. Trophos is currently enrolling patients in a European Phase IIa trial to assess the efficacy of TRO19622 in painful diabetic neuropathy and expects to begin a Phase II/III trial in ALS in 2008.
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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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Trophos SA, a biopharmaceutical company specializing in the discovery and development of drugs for neurological disorders, announced today that a publication entitled “Identification and characterization of TRO19622 (cholest-4-en-3-one, oxime), a novel drug candidate for amyotrophic lateral sclerosis” has been accepted and published online May 11, 2007 in the Journal of Pharmacology And Experimental Therapeutics.

The studies reported in the paper by Bordet et al., (see below) identify two protein targets of TRO19622 present in the outer mitochondrial membrane suggesting that the compound has potential in a range of additional commercially attractive therapeutic indications involving mitochondrial dysfunction, including painful neuropathies. The publication describes the models of motor neuron disease employed to support the use of this compound to treat ALS, as well as spinal muscular atrophy. TRO19622 is currently in a Phase IIa clinical trial to establish its efficacy as a treatment for painful diabetic neuropathy.
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Families of Spinal Muscular Atrophy (FSMA) is pleased to announce the selection of a Clinical Candidate for Spinal Muscular Atrophy through its program being conducted at deCODE chemistry. At the same time FSMA is now extending its contract with deCODE to continue work towards an Investigational New Drug (IND) application with the Food and Drug Administration. If successful, this would be the first novel drug designed specifically to treat Spinal Muscular Atrophy (SMA).

SMA is a genetic disorder with no current treatment that is the leading killer of children under two years of age. SMA is typically marked by the degeneration of voluntary muscle movement including the muscles that control crawling, walking, swallowing or breathing. This is an important step in the development of a small molecule therapeutic for this debilitating and normally fatal disease.
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Brief summaries of presentations by 16 leading SMA researchers at the 2007 Fight SMA Conference are available here.

OrphageniX Inc., a new biotechnology company founded by University of Delaware researchers, has been established in Wilmington to develop and commercialize University of Delaware-patented technologies for repairing genes that cause rare, hereditary diseases such as sickle cell anemia and spinal muscular atrophy. The announcement was made in a news release issued by the company on April 13.

Eric Kmiec, professor of biological sciences, and Hetal Parekh-Olmedo, senior research associate, both in the UD College of Arts and Sciences, co-founded and incubated OrphageniX at UD’s Delaware Biotechnology Institute in the Delaware Technology Park in 2005. Kmiec holds 14 UD patents for gene-editing technologies and is widely regarded as a pioneer in the field.

There are more than 5,000 rare or “orphan” diseases, so named because each affects fewer than 200,000 people nationwide. A number of these diseases are caused by a single-point mutation in a gene–which is like a spelling error, a single “letter” out of place, in its DNA code. The DNA nucleotide adenine (A), for example, might be replaced by guanine (G), cytosine (C) or thymidine (T).
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Fight SMA has a new partner in its search for a treatment or cure for spinal muscular atrophy (SMA). The international nonprofit organization has established a research and development collaboration with PTC Therapeutics, Inc (PTC) to identify and develop a compound that can be used to treat SMA. SMA is the leading genetic cause of infantile death, yet there currently is no treatment available. PTC Therapeutics, Inc. is a biopharmaceutical company focused on the discovery and development of orally administered, proprietary small-molecule drugs that target post-transcriptional control processes, and has made great strides toward developing compounds for a variety of genetic disorders including cystic fibrosis (CF) and Duchenne muscular dystrophy (DMD).

“This is an exciting opportunity to push toward a treatment for SMA,” said Dr. Christian Lorson, PhD, Scientific Director of FightSMA. “The unique genetic context of SMA is well-suited for the type of therapeutic intervention in which PTC Therapeutics specializes, and with the highly skilled scientists at PTC, we are hopeful that great strides can be made towards identifying a drug for this devastating disease.”

“We’re thrilled that PTC Therapeutics is committed to the fight,” said Fight SMA President Martha Slay. “The team at PTC is dedicated and experienced. Theirs is an incredible combination of talent and determination to see these therapies delivered to children and adults suffering with SMA.”
Read the press release on the Fight SMA blog

Families of Spinal Muscular Atrophy (FSMA) and Paratek Pharmaceuticals, Inc. today announced they have extended their joint R&D collaboration to develop a drug candidate for the treatment of Spinal Muscular Atrophy (SMA), the leading genetically inherited cause of death of children under the age of two years. The collaboration is focused on optimizing and advancing into the clinic a novel small molecule within Paratek’s library derived from the tetracycline class of compounds.
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RNA splicing antisense technology studied at Cold Spring Harbor Laboratory (CSHL) effectively corrected an mRNA splicing defect found in spinal muscular atrophy (SMA) patients, and is now ready to be tested in mouse models.  “SMA patients who suffer from motor-neuron degeneration may benefit from our ability to correct the mRNA splicing defect that makes their SMN2 genes only partially functional,” suggested CSHL Professor Adrian Krainer, Ph.D.

RNA splicing antisense technology allows researchers to influence the ultimate structure and function of proteins. Proteins are synthesized from instructions coded in the DNA through a multi-step process that includes RNA splicing.  Information stored in the DNA of genes is transcribed into immature “pre-messenger RNAs” (pre-mRNAs), pre-mRNAs are then spliced into mature “messenger RNAs” (mRNAs), and finally, mRNAs are translated into proteins.  In humans and most other organisms, the splicing process thus ensures proper protein production. 
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Drug therapy can extend survival and improve movement in a mouse model of spinal muscular atrophy (SMA), new research shows. The study, carried out at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS), suggests that similar drugs might one day be useful for treating human SMA.

“This study shows that treatment can be effective when started after the disease appears,” says Kenneth H. Fischbeck, M.D., of the NINDS, who helped lead the new study. The finding is important because most children with SMA are diagnosed after symptoms of the disease become obvious, he adds. The report appears in the February 22, 2007, advance online publication of The Journal of Clinical Investigation.
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In a small, dimly lit room at Primary Children’s Medical Center, Liam Russell’s small hands tremble. His thick hair tousled from his winter hat, the toddler watches SpongeBob SquarePants on a portable DVD player as strangers swarm around him.

Under the spell of sedation, Liam hardly notices the metal barbs neurologist Kathryn Swoboda gently presses into his right wrist, or the electric shocks stimulating his ulnar nerve. His eyelids heavy, he fidgets with the electrode taped to his right hand as it measures the nerve’s response and spits out wavy lines on a computer screen.
The 2-year-old endures such testing as one of the first and youngest children in the country trying an experimental drug treatment for spinal muscular atrophy, a crippling genetic disorder.

Swoboda, an assistant professor at the University of Utah School of Medicine, is the principal investigator of a one-year, $2.5 million clinical trial to study the drugs’ effectiveness in 90 children, ages 2 to 17.
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Trophos, a biopharmaceutical company specialising in the discovery and development of drugs for neurodegenerative diseases, announced today the successful completion of Phase Ib clinical studies for its lead compound TRO19622. The completed studies include a one month compliance, tolerance and safety study conducted in 36 ALS patients at doses of 125 mg, 250 mg and 500 mg administered orally, once a day, plus two drug-drug interaction studies conducted in healthy volunteers. TRO19622 is in clinical development for motoneuron diseases, amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease) and spinal muscular atrophy (SMA), as well as for painful diabetic neuropathy.

The studies demonstrated that, in ALS patients, TRO19622 is well tolerated and exceeded the exposure level predicted to achieve efficacy via the oral route at doses =250mg per day. In healthy volunteers, TRO19622 exposure levels were approximately 30% higher after repeated dosing with riluzole for which bioequivalence was shown before and after repeated dosing with TRO19622. In these three Phase Ib studies, TRO19622 continues to demonstrate an excellent clinical safety profile in all subjects receiving drug substance.
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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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Spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality. SMA is caused by the homozygous absence of survival motor neuron-1 (SMN1). SMN2, a nearly identical copy gene, is retained in all SMA patients and encodes an identical protein as SMN1; however, SMN1 and SMN2 differ by a silent C to T transition which results in the production of an alternatively spliced isoform (SMNDelta7), which encodes a defective protein, demonstrating that the absence of the short peptide encoded by SMN exon 7 is critical in SMA development. Previously, we have shown that for some functions heterologous sequences can compensate for the exon 7 peptide, suggesting that the SMN C-terminus functions non-specifically. Consistent with this hypothesis, we now identify novel aminoglycosides that can induce SMN protein levels in patient fibroblasts. This hypothesis was supported, in part, by a novel fluorescent SMN read-through assay. Interestingly, however, through the development of a SMN exon 7-specific antibody, results suggested that levels of normal full-length SMN might also be elevated by aminoglycoside treatment. These results demonstrate that the compounds that promote read-through may provide an alternative platform for the discovery of compounds that induce SMN protein levels.
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OBJECTIVE: To assess the efficacy of phenylbutyrate (PB) in patients with spinal muscular atrophy in a randomized, double-blind, placebo-controlled trial involving 10 Italian centers. METHODS: One hundred seven children were assigned to receive PB (500 mg/kg/day) or matching placebo on an intermittent regimen (7 days on/7 days off) for 13 weeks. The Hammersmith functional motor scale (primary outcome measure), myometry, and forced vital capacity were assessed at baseline and at weeks 5 and 13. RESULTS: Between January and September 2004, 107 patients aged 30 to 154 months were enrolled. PB was well tolerated, with only one child withdrawing because of adverse events. Mean improvement in functional score was 0.60 in the PB arm and 0.73 in placebo arm (p = 0.70). Changes in the secondary endpoints were also similar in the two study arms. CONCLUSIONS: Phenylbutyrate was not effective at the regimen, schedule, and duration used in this study.
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VASTox [now Summit plc], a leading UK biotechnology company, announces today that it has received a grant from the Association Francaise Contre Les Myopathies (AFM), a leading European neuromuscular disease charity, to support to the company’s Spinal Muscular Atrophy (SMA) drug discovery programme.

VASTox has developed an innovative in vivo screen, which models SMA in fruitfly larvae (Drosophila melanogaster). The Company is using this model to identify small molecules from its proprietary compound library. The financial support from AFM will allow VASTox to accelerate the preclinical screening and candidate identification phase of the programme and consequently aid the development of a novel therapy for SMA.

Spinal Muscular Atrophy affects 50,000 people in the developed world and is a genetic disease that causes loss of motor neurons in the spinal cord resulting in muscle atrophy. Patients either do not acquire or progressively lose the ability to move and death primarily occurs due to respiratory failure. In its severest form, known as type I, life expectancy is often less than two years.

AFM is one of the largest charities in the World that focuses on neuromuscular diseases; it has raised over €1.2 billion since 1987, the majority of which has been devoted to research and development. Founded in 1958 by a group of muscular dystrophy patients and families, AFM is focused mainly on developing cures for neuromuscular diseases and reducing the disabilities they cause.

Steven Lee, PhD, CEO of VASTox said: ”VASTox is delighted to receive this grant from the AFM to help us accelerate our spinal muscular atrophy drug discovery efforts, particularly following the exciting progress we announced in the SMA programme last month. It is recognition that our unique, fruitfly-based approach to SMA research offers the potential for a novel treatment for this lethal disease. This is VASTox’s first charitable grant and we will work closely with the AFM and other like-minded charities to accelerate our drug discovery efforts wherever possible.”
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VASTox [now Summit plc], a leading UK biotechnology company, has presented exciting progress in its spinal muscular atrophy (SMA) drug discovery programme. VASTox’s Head of Biology, Dr Jon Tinsley, presented the data at the Society for Neuroscience annual meeting, Neuroscience 2006, held in Atlanta, GA, USA, from the 14-18 October 2006.

The Company has discovered a number of promising ‘hits’ from a proprietary collection of drug-like molecules, which have been shown to improve the symptoms of SMA in an in vivo fruitfly (Drosophila melanogaster) screen designed to model the disease. The speed with which these hit molecules were identified by screening directly in a genetically-modified fruitfly is an important validation of VASTox’s innovative approach towards drug discovery. This progress will allow the Company to rapidly advance the SMA programme into the lead optimisation phase of pre-clinical development early in 2007, only 18 months after the programme was initiated.

SMA is a severe genetic neurological disease that causes a progressive loss of motor neurons in the spinal cord leading to severe muscle atrophy. SMA patients either do not acquire or eventually lose the ability to move and death occurs primarily as a result of fatal respiratory insufficiency.

SMA is the leading genetic cause of mortality in infants and toddlers in the World. It affects 1 in 6,000 newborns, an incidence comparable to that of other ‘common’ rare diseases, including Cystic Fibrosis, Duchenne Muscular Dystrophy and Sickle Cell Anaemia. There are an estimated 50,000 SMA sufferers in the developed World.

Steven Lee, PhD, CEO of VASTox said: ”These results from our spinal muscular atrophy programme illustrate the ‘in vivo advantage’ of VASTox’s approach to drug discovery. By using fruitflies and zebrafish at the earliest stages of drug discovery, we are dramatically reducing the time and resources needed and we believe, significantly increasing the chances of producing a drug which is safe in man. SMA is a deadly genetic disease affecting children and our approach towards developing a therapy is both innovative and unparalleled.”
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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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CHICAGO (Reuters) – Merck & Co. Inc. on Monday said U.S. regulators approved the drugmaker’s new treatment for a form of non-Hodgkin’s lymphoma in patients who have failed other therapies. Merck said the U.S. Food and Drug Administration approved the treatment, called Zolinza, for patients with cutaneous T-cell lymphoma for those with progressive, persistent or recurrent forms of the disease. Zolinza, also known as vorinostat or suberoylanilide hydroxamic acid (SAHA), is in a new class of anti-cancer therapies called histone deacetylase (HDAC) inhibitors. Histone deacetylation is thought to be a mechanism for silencing some tumour suppressor genes and other genes responsible for cell cycle progression, cell proliferation, apoptosis and differentiation.
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When Elizabeth Lee Hallam was born on Sept. 29, 2003, she was a textbook example of the perfect baby. But by 8 months of age, she was battling a fatal genetic disease her family had never heard of. Elizabeth was diagnosed with the most acute form of spinal muscular atrophy, a motor neuron disorder similar to Lou Gehrig’s disease that afflicts one in 6,000 babies. With no cure or treatment, the doctor predicted Elizabeth – like 95 percent of all SMA babies – would not live more than two years.

“I screamed when we got the news,” said her grandmother, Jeanna Huette, 48. “I could not understand how such a beautiful child could just die. I cried for a few more days … and then I knew I had to save her.” As Elizabeth approaches her third birthday, she cannot sit, stand, crawl or walk and relies on machines to swallow, get nourishment and even cough. But she is alive and improving.

Her family enrolled Elizabeth in a trial designed to test the safety and effectiveness of the drug hydroxyurea against SMA. It is one of only a few clinical studies on the disease approved by the Food and Drug Administration and is run by Dr. Ching Wang, a scientist affiliated with Stanford University who has made conquering the disease his life’s work.
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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.
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In June the 10th Annual Spinal Muscular Atrophy Research Group Meeting was held in Montreal, Canada. Over 160 researchers and clinicians attended. Scientific sessions were held on the following topics: Clinical Trials, Outcome Measures, Stem Cell Therapies, SMN Functions, and Drug Discovery Programs. Over 80 presentations were given. A detailed overview of each session is provided below.

We would like to take this opportunity to highlight several particularly relevant research developments separately. These include the development of novel clinical trial outcome measures for both Type I and ambulatory Type III patients, which will allow future trials to enrol additional SMA patient types. On the basic research front, one the most interesting highlights was new data presented by multiple labs indicating that SMN has a specific function in neurons and that the role of SMN in the cell body is likely different than its role in motor axons. This is important because delineating and understanding the importance of the specific role of SMN in axons will facilitate more strategic design of drug discovery screens. Drs. Hans Keirstead and Doug Kerr also gave exciting talks on stem cell therapies for SMA. Dr. Kerr showed that mice motor neurons derived from mouse stem cells send axons out of the spinal column into the periphery when injected into the spinal cord. These motor axons can form functional connections on muscles, which provided clinical improvement in mice with motor neuron disease. Moreover, Dr. Keirstead reported good progress on developing stem cell-derived motor neurons for human trials. Finally, there were a number of talks focusing on drug discovery efforts to find novel small molecule therapies for SMA. Talks on this topic were given by representatives of the labs of deCODE Chemistry, Christina Brahe, Brunhilde Wirth, Brent Stockwell, the NINDS SMA project, and Trophos. The initiative on up-regulating SMN levels in SMA that is closest to the clinic was given by deCODE Chemistry.
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A complex combination of treatments, including stem cells and growth factors, can heal damaged neural circuits, allowing partially paralyzed rats to walk. These findings represent a significant step forward in regenerative medicine, providing new treatment possibilities for Amyotrophic Lateral Sclerosis (ALS) and other neurodegenerative diseases, as well as some types of spinal-cord injury.

“This work is a major stepping-stone to human application of stem-cell transplant approaches,” says Hans S. Keirstead, co-director of the Stem Cell Research Center at the University of California, Irvine. He says that the ability to grow new neural fibers out of the spinal cord “renders transplantation approaches to repair realistic.”

Previous research has shown that cell transplants and other treatments can help paralyzed rodents walk. But those experiments have focused mainly on repairing local damage within the spinal cord. They could help patients whose motor neurons — cells carrying messages from brain to spinal cord — remain intact after injury or disease.

In contrast, the current study, conducted by a team of scientists at Johns Hopkins University, focused on a longer-distance repair problem. It is the first study to show that newly grown nerve fibers can emerge from the spinal cord, extend all the way to the muscle, then form functional connections with muscle. This feat is particularly important for ALS and other disorders characterized by the loss of motor neurons. “Some may have thought this was a bridge you can’t cross,” says David Owens, research director at the National Institutes of Neurological Disorders and Stroke, which sponsored the study.
Read the full article in Technology Review (includes links to before/after video clips)

The before/after video is also viewable via Youtube:

Links to other articles on this breakthrough:

• Neurons Grown From Embryonic Stem Cells Restore Function In Paralyzed Rats
• Hopkins Scientists Use Embryonic Stem Cells, New Cues To Awaken Latent Motor Nerve Repair

An epilepsy drug that has been on the market for decades can ease the symptoms of adult sufferers with a genetic disorder that seriously weakens muscles.

Scientists at Washington University School of Medicine in St. Louis retrospectively reviewed results from off-label use of the drug valproate to treat seven adult spinal muscular atrophy (SMA) patients. Clinicians offered the drug to patients on the basis of research conducted elsewhere that showed the drug increased levels of a key protein in cell cultures.

“The treatment has been fairly successful,” says lead author Chris Weihl, M.D., Ph.D., a postdoctoral fellow in neurology. “The drug appeared to be well-tolerated and increased the strength of the patients who took it.”

The study, now available online, will appear in the August 8 issue of Neurology.

Weihl notes that a larger, prospective trial is needed to firmly establish valproate as a treatment of choice for sufferers of this type of SMA.

Such trials are already underway elsewhere in pediatric patients who suffer from a different type of SMA that begins earlier in life. Weihl and his colleagues are concerned that valproate may not work as well in those patients. They wanted to make sure that researchers did not discard the possibility that valproate could help older sufferers even if the trials in pediatric patients went poorly.
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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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The Spinal Muscular Atrophy Foundation today announced that they have initiated a research and development collaboration with PTC Therapeutics, Inc. (PTC). The collaboration is designed to leverage PTC’s proprietary Gene Expression Modulation by Smallmolecules (GEMS) technology to identify and develop new small molecule therapeutics for use in the treatment or prevention of spinal muscular atrophy (SMA), a neuromuscular disease and the leading genetic cause of death among infants and toddlers. Under the terms of the agreement, the SMA Foundation will provide up to $1.6 million in funding to PTC based upon completion of certain milestones.

“PTC has demonstrated a strong commitment to SMA and other pediatric orphan diseases,” said Loren Eng, President of the SMA Foundation. “We believe PTC’s scientific assets and proven accomplishments make them an ideal partner in our efforts to identify treatments for SMA.”
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Among a panel of histone deacetylase (HDAC) inhibitors investigated, suberoylanilide hydroxamic acid (SAHA) evolved as a potent and non-toxic candidate drug for the treatment of spinal muscular atrophy (SMA), an alpha-motoneurone disorder caused by insufficient survival motor neuron (SMN) protein levels. SAHA increased SMN levels at low micromolar concentrations in several neuroectodermal tissues, including rat hippocampal brain slices and motoneurone-rich cell fractions, and its therapeutic capacity was confirmed using a novel human brain slice culture assay. SAHA activated survival motor neuron gene 2 (SMN2), the target gene for SMA therapy, and inhibited HDACs at submicromolar doses, providing evidence that SAHA is more efficient than the HDAC inhibitor valproic acid, which is under clinical investigation for SMA treatment. In contrast to SAHA, the compounds m-Carboxycinnamic acid bis-Hydroxamide, suberoyl bishydroxamic acid and M344 displayed unfavourable toxicity profiles, whereas MS-275 failed to increase SMN levels. Clinical trials have revealed that SAHA, which is under investigation for cancer treatment, has a good oral bioavailability and is well tolerated, allowing in vivo concentrations shown to increase SMN levels to be achieved. Because SAHA crosses the blood-brain barrier, oral administration may allow deceleration of progressive alpha-motoneurone degeneration by epigenetic SMN2 gene activation.
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“This new drug development collaboration will focus on optimizing the drug features of a newly identified lead compound that directly influences SMN2 gene splicing,” said Dr. Jill Jarecki, FSMA Research Director. “FSMA-sponsored research has contributed to the identification of the SMN1 gene as well as a second disease-modifying copy of the gene called SMN2. Normally, the SMN2 gene produces reduced amounts of SMN protein due to a defect in mRNA splicing. This project aims to develop a SMA drug that safely and effectively restores the proper amount of SMN protein in the body in order to slow or reverse the disease process by correcting the splicing of SMN2 gene.” Read the rest of this entry »

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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by Brunhilde Wirth
Institute of Human Genetics of the University of Cologne, Germany

Here we report on our paper entitled “In vivo activation of SMN in SMA carriers and patients treated with valproate” by Brichta L, Holker I, Haug K, Klockgether T & Wirth B. Annals of Neurology, 2006, April 10, advanced online publication.

In July 2003, we reported that valproic acid (VPA) was able to increase full-length SMN2 transcript and protein levels by 2fold to 4fold in fibroblasts derived from SMA patients (Brichta et al. Hum Mol Genet, 2003). Similar results were shown by the group of K. Fischbeck and published in November 2003 (Sumner et al., Ann Neurol 2003). Furthermore, we have been able to demonstrate that VPA significantly increases SMN RNA/protein levels in cultured brain slices from rat and humans (obtained after surgery of epilepsy patients) as well as in cultured rat embryonic motor neurons (Hahnen et al., J Neurochemistry, 2006, in press).

VPA is a well-explored FDA-approved drug that rarely shows any severe side effects in long-term therapy of epilepsy patients. This makes it available for a straightforward application in humans.

Meanwhile, we studied the effect of VPA in blood from SMA carriers and patients to address the following questions: (1) Is VPA capable of acting on the in vivo FL-SMN transcript/protein level, and (2) how suitable is the use of blood for the development of a biomarker that would allow monitoring of the drug response in VPA-treated SMA patients?
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Trophos is a biopharmaceutical company founded in 1999 to discover and develop new drugs to treat neurodegenerative disorders. Today, Trophos focuses its expertise on two motor neuron diseases, amyotrophic lateral sclerosis (ALS or Lou Gehrig’s Disease) and spinal muscular atrophy (SMA), as well as Huntington’s disease (HD). Trophos has also developed expertise and offers screening services for targets implicated in Alzheimer’s disease.

WHAT IS TRO19622, HOW WAS IT DISCOVERED, WHAT IS ITS DEVELOPMENT STATUS?
TRO19622 is a new chemical entity derived from the Trophos compound collection. The molecule has a cholesterol-like structure and displays remarkable neuroprotective properties both in vitro and in vivo. It was discovered thanks to the original high-throughput screening platform using primary motor neurons that Trophos developed to support its drug discovery strategy. TRO19622 is as effective as a cocktail of three neurotrophic factors in keeping
motor neurons alive in culture. TRO19622 also improves survival of striatal neurons in a cell-based model of Huntington’s disease and displays anti-apoptotic properties for other types of primary neurons. In vivo, TRO19622 is active in several preclinical models of neurodegenerative disease.
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Families of Spinal Muscular Atrophy today announced the funding of an industrial research program at Cambria Bisosciences LLC to identify novel therapeutic targets for Spinal Muscular Atrophy (SMA). Cambria will utilize the model organism Caenorhabditis elegans to mimic genetic aspects of SMA.

“It is now well established that the loss of the SMN1 gene leads to motor neuron loss and muscle degeneration in SMA patients and that the number of SMN2 gene copies modulates disease severity,” said Dr. Beth Westlund of Cambria Biosciences and lead researcher on this project. “Additional studies suggest that other genes can affect the onset and severity of motor neuron loss in this condition. The focus of our research will be to search for genes that can alleviate the problems associated with defects in SMN1 using the roundworm Caenorhabditis elegans or C. elegans, which is a very powerful model organism that is widely used by scientists to identify novel genetic interactions.
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Humans have two nearly identical copies of the Survival Motor Neuron (SMN) gene, SMN1 and SMN2. In spinal muscular atrophy (SMA), SMN2 is not able to compensate for the loss of SMN1 due to exclusion of exon 7. Here we describe a novel inhibitory element located immediately downstream of the 5′ splice site in intron 7. We call this element intronic splicing silencer N1 (ISS-N1). Deletion of ISS-N1 promoted exon 7 inclusion in mRNAs derived from the SMN2 minigene. Underlining the dominant role of ISS-N1 in exon 7 skipping, abrogation of a number of positive cis elements was tolerated when ISS-N1 was deleted. Confirming the silencer function of ISS-N1, an antisense oligonucleotide against ISS-N1 restored exon 7 inclusion in mRNAs derived from the SMN2 minigene or from endogenous SMN2. Consistently, this oligonucleotide increased the levels of SMN protein in SMA patient-derived cells that carry only the SMN2 gene. Our findings underscore for the first time the profound impact of an evolutionarily nonconserved intronic element on SMN2 exon 7 splicing. Considering that oligonucleotides annealing to intronic sequences do not interfere with exon-junction complex formation or mRNA transport and translation, ISS-N1 provides a very specific and efficient therapeutic target for antisense oligonucleotide-mediated correction of SMN2 splicing in SMA.
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Trophos, a biopharmaceutical company specialising in the discovery and development of drugs for neurodegenerative diseases, announced today the successful completion of Phase I clinical trials for its lead compound TRO19622.

TRO19622 is representative of a class of novel compounds identified using the proprietary neuronal cell screening platform developed at Trophos. In preclinical studies, these compounds have been demonstrated to promote the survival of a wide range of neurons in vitro, as well as in several in vivo models of neurodegenerative diseases. The clinical trials were conducted in France and involved single and multiple dose studies on healthy adult subjects. TRO19622 was demonstrated to: i) be well tolerated; ii) have achieved the effective clinical dose via the oral route and, iii) have an excellent safety profile.

The successful completion of Phase I means that Trophos now expects to initiate a pivotal Phase II/III clinical trial for the ALS indication in Q4 2006. The trial will be conducted in the USA and Europe. TRO19622 has already been granted orphan drug designation status for the treatment of Amyotrophic Lateral Sclerosis (ALS) in the USA, and for the treatment of Spinal Muscular Atrophy (SMA) in the EU.
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Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an infantile autosomal-recessive motor neuron disease caused by mutations in the immunoglobulin micro-binding protein 2. We investigated the potential of a spinal cord neural stem cell population isolated on the basis of aldehyde dehydrogenase (ALDH) activity to modify disease progression of nmd mice, an animal model of SMARD1. ALDH(hi)SSC(lo) stem cells are self-renewing and multipotent and when intrathecally transplanted in nmd mice generate motor neurons properly localized in the spinal cord ventral horns. Transplanted nmd animals presented delayed disease progression, sparing of motor neurons and ventral root axons and increased lifespan. To further investigate the molecular events responsible for these differences, microarray and real-time reverse transcription-polymerase chain reaction analyses of wild-type, mutated and transplanted nmd spinal cord were undertaken. We demonstrated a down-regulation of genes involved in excitatory amino acid toxicity and oxidative stress handling, as well as an up-regulation of genes related to the chromatin organization in nmd compared with wild-type mice, suggesting that they may play a role in SMARD1 pathogenesis. Spinal cord of nmd-transplanted mice expressed high transcript levels for genes related to neurogenesis such as doublecortin (DCX), LIS1 and drebrin. The presence of DCX-expressing cells in adult nmd spinal cord suggests that both exogenous and endogenous neurogeneses may contribute to the observed nmd phenotype amelioration.
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deCODE chemistry and Families of Spinal Muscular Atrophy (FSMA) today announced a renewal of their collaboration to develop a small molecule therapeutic for spinal muscular atrophy, a genetic disorder that is the leading killer of children under two years of age. Initiated in 2003, the deCODE chemistry-FSMA collaboration focused on optimization of a class of molecule that was discovered in a high-throughput, cell-based phenotypic assay developed under sponsorship by FSMA. By providing services for lead optimization and in-house support of the phenotypic assay, deCODE chemistry has developed optimized analogues that have high potency in the assay, excellent metabolic stability, efficient penetration of the blood-brain barrier, and an attractive pharmacokinetic profile. The focus of the collaboration in the coming year will be to further assess the pharmaceutical properties of lead candidates and select a small number of analogues for IND-directed, pre-clinical development. Read the rest of this entry »

Invitrogen Corporation and Families of Spinal Muscular Atrophy (FSMA) today announced a new collaboration to identify biological targets that are linked to the causes and symptoms of Spinal Muscular Atrophy (SMA). Financial terms of the collaboration were not disclosed. SMA is a genetic disorder that causes a chronic deficiency in the production of the Survival Motor Neuron (SMN) protein. This protein is essential to the proper functioning of the motor neurons that originate in the spinal cord, as well as control of muscles in the limbs, neck and chest. In the United States alone there are more than seven million carriers of the genetic risk factors for SMA–and the disease affects approximately one in every 6,000 live births. SMA is usually diagnosed at less than 18 months of age.

The initial stages of this collaboration will be performed by Invitrogen scientists utilizing the company’s proprietary ProtoArray protein microarray technology. Approximately 3,000 human proteins and 5,000 yeast proteins will be rapidly screened as potential targets for SMA therapeutic intervention. This work will build upon the successful identification of compounds that up-regulate SMN levels in an ongoing FSMA sponsored drug discovery program at deCODE Genetics.
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Mutations in one of the duplicated survival of motor neuron (SMN) genes lead to the progressive loss of motor neurons and subsequent development of spinal muscular atrophy (SMA), a common, and usually fatal, hereditary disease. Homozygous absence of the telomeric copy (SMN1) correlates with development of SMA because differential splicing of the centromeric copy (SMN2) leads to exon 7 skipping and predominantly produces a biologically inactive protein isoform. To increase exon 7 inclusion of SMN2, we have designed a series of vectors that express modified U7 snRNAs containing antisense sequences complementary to the 3′ splice site of SMN exon 8. Over 20 anti-SMN U7 snRNAs were tested for their ability to promote exon 7 inclusion in the SMN2 gene. Transient expression of anti-SMN U7 snRNAs in HeLa cells modulated SMN2 splicing to approximately 70% exon 7 inclusion in a sequence-specific and dose-dependent manner. Significantly, the administration of anti-SMN U7 snRNPs results in an increase in the concentration of SMN protein. These results suggest that modulation of SMN2 pre-mRNA splicing by modified U7 snRNAs provides a promising form of gene therapy for the treatment of SMA.
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by Michelle AuCoin and Hans S. Keirstead, Ph.D. (From FSMA newsletter, Winter 2005)

Although treatment can ease complications of SMA, no cure exists. Still, the NIH has deemed SMA one of the neurological genetic conditions closest to an effective treatment or cure in the near future. To date, the primary approaches to treating or curing SMA have focused on two strategies. First, genetic therapy – manipulating the genetic material responsible for producing SMA. Second, cellular replacement therapy – replacing dead or dying motor neurons with new ones.

Human embryonic stem cells (hESCs) offer great promise for cellular replacement strategies due to their ability to generate every cell in the body (every human is made from their hESCs), and their seemingly unlimited ability to replicate themselves (allowing for huge numbers of cells to be generated). The ability to amplify hESCs to enormous numbers already exists. Generating medically useful cell populations from hESCs has been one of the largest obstacles facing hESC researchers. How do we coax hESCs to become the one cell type that we desire for treatment of a human disease? For the first time, the Keirstead Research Group at University of California at Irvine has produced high purity cells from hESCs.
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What we know is that low levels of the protein SMN, Survival Motor Neuron, cause SMA, and we know that SMN forms a complex with RNA in all cell types. In motor neurons SMN is found in two different types of complexes. It is found in complexes in the nucleus, and it is found in complexes out in the axon. So we know that the low levels of SMN cause motor neurons to die, but what we do not know at this point is what is the critical function of SMN in the motor neuron. Is it dysfunction up in the nucleus or is it some specialized function to motor neurons, which are out in the axon? It could very well be that SMN is essential in both of these places for function of the motor neurons. This is still an open debate in the SMA research field, and a number of presentations yesterday, addressed these questions.

FSMA has taken a three-pronged approach in its research activities. The first is the funding of basic research grants. The second is to fund drug discovery efforts, and we have some substantial work going on with deCODE genetics, the third area – funding clinical testing, and the development of testing protocols for drugs that may come down the line. To address these activities FSMA is funding 29 basic research grants in 2005 alone, one of the major roles is try to elucidate the biological basis of SMA. This is really important because this will guide all the therapeutic strategies. When developing therapies we want to take a rational approach, and in order to do that you need to have a good understanding of what the molecular basis of the disease is. Another thing we would like to understand is how SMN expression is regulated because we know that low levels of SMN cause SMA, so if we understand how it is regulated, we can manipulate those pathways in order to cause more SMN to be produced. This is a basic drug discovery strategy. FSMA also funds research that assesses new potential SMA therapies. The current therapies have been focused on increasing SMN levels, but there may be other ways to mitigate SMA symptoms, and I think it is very important to explore this through basic research.
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Slides from the research update can be found here (PowerPoint file)

Howard Hughes Medical Institute (HHMI) researchers have deciphered a key part of the regulatory code that governs how motor neurons in the spinal cord connect to specific target muscles in the limbs.

The researchers said that understanding this code may help guide progress in restoring motor neuron function in people whose spinal cords have been damaged by trauma or disease. The studies suggest that the code—which involves members of the family of transcription factors encoded by the Hox genes—could also govern the establishment of other spinal cord circuits. This circuitry includes interneurons that control motor neuron firing patterns and sensory neurons that transmit feedback information on muscle action.
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Ching Wang, MD, PhD, didn’t sign up for his pediatric neurology residency in 1990 to watch children die. But, as in nearly any medical specialty, there are some fatal diseases for which no effective treatment exists. Frustrated after delivering grim news to one too many sets of parents, Wang vowed to do something. He went back into the lab to learn more about spinal muscular atrophy, or SMA, and has spent the last 15 years researching the condition, which is the most common genetic disorder responsible for the deaths of children under two. . . .

Wang has been involved in identifying the cause of the disorder, cloning the responsible gene and modifying its expression. Now he’s the senior author on a research article that was published in the August issue of the Annals of Neurology that shows the genetic defect can be overcome in human cells with the condition.
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Spinal muscular atrophy (SMA) is a motor neuron disease caused by dysfunction of the survival motor neuron (SMN) gene. Human SMN gene is present in duplicated copies: SMN1 and SMN2. More than 95% of patients with SMA lack a functional SMN1 but retain at least one copy of SMN2. Unlike SMN1, SMN2 is primarily transcribed into truncated messenger RNA and produces low levels of SMN protein. We tested a therapeutic strategy by treating cultured lymphocytes from patients with SMA with hydroxyurea to modify SMN2 gene expression and to increase the production of SMN protein. Twenty lymphoblastoid cell lines (15 SMA and 5 control lines) were treated with hydroxyurea at 5 concentrations (0.5, 5, 50, 500, and 5,000 microg/ml) and 3 time points (24, 48, and 72 hours). SMN2 gene copy numbers were determined using real-time quantitative polymerase chain reaction. Hydroxyurea treatment resulted in a time-related and dose-dependent increase in the ratio of full-length to truncated SMN messenger RNA. SMN protein levels and intranuclear gems also were significantly increased in these hydroxyurea-treated cells. The SMN2 gene copy number correlated inversely with the SMA phenotypic severity. This study provides the first evidence for a therapeutic indication of hydroxyurea in SMA.
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Several studies indicate that physical exercise is likely to be neuroprotective, even in the case of neuromuscular disease. In the present work, we evaluated the efficiency of running-based training on type 2 spinal muscular atrophy (SMA)-like mice. The model used in this study is an SMN (survival motor neuron)-null mouse carrying one copy of a transgene of human SMN2. The running-induced benefits sustained the motor function and the life span of the type 2 SMA-like mice by 57.3%. We showed that the extent of neuronal death is reduced in the lumbar anterior horn of the spinal cord of running-trained mice in comparison with untrained animals. Notably, exercise enhanced motoneuron survival. We showed that the running-mediated neuroprotection is related to a change of the alternative splicing pattern of exon 7 in the SMN2 gene, leading to increased amounts of exon 7-containing transcripts in the spinal cord of trained mice. In addition, analysis at the level of two muscles from the calf, the slow-twitch soleus and the fast-twitch plantaris, showed an overall conserved muscle phenotype in running-trained animals. These data provide the first evidence for the beneficial effect of exercise in SMA and might lead to important therapeutic developments for human SMA patients.
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MDA grantee Christian Lorson at the University of Missouri was on a team that found that exposing cells carrying a mutation that causes spinal muscular atrophy (SMA) to drugs in the aminoglycoside family helps them produce more of the needed SMN protein, a lack of which leads to SMA.

One way to explain the increase, Lorson says, is that a molecular “tail” is added to the short, relatively unstable form of SMN that SMA-affected cells make, making it more like the full-length form of SMN that they lack. Aminoglycosides are known to allow cells to “read past” certain genetic stop signals and thereby produce longer protein molecules.

Although this seems a likely explanation, Lorson notes that there are other possibilities. “It may be that we are interfering with the cell’s normal pathway for protein degradation, or that some other protein, such as an SMN binding protein, is altered by the drug and can then stabilize the short SMN protein.”

In a paper published in the May 1 issue of Human Molecular Genetics, the investigators say that the aminoglycoside effect “identifies a possible alternative approach for therapeutic intervention” in SMA.
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At 3, Anna Rose Scurria stands tentatively, her eyes big and smile a little apprehensive. Her mom, Krista Scurria, stands close, not quite touching her, but you can see an invisible thread as she forms herself around her daughter so she can catch her quickly should the child falter.

Anna Rose and her brother Joshua, almost 6, both have spinal muscular atrophy, the leading genetic killer of children younger than 2. Only within the past year has she been able to stand and take nervous little steps with a walker. Her parents give credit for that and the fact that Joshua can now straighten himself in his wheelchair to an experimental treatment.

Parents like Krista and John Scurria of Louisiana, as well as Loree and Ward Weisman of Colorado, have been bringing their children to Utah regularly recently for a monitored clinical study. Lyza Weisman is also, at 3, beginning to walk again. Like the Scurrias, the Weismans use the word “miracle” to describe what they’ve experienced in the early phase clinical trials testing new use of two proven medications — sodium phenylbutyrate and valproic acid combined with carnitine. Read the rest of this entry »

Summary of research presentation by Adrian Krainer (Cold Spring Harbor Laboratory, NY) at the 2005 FightSMA conference

The SMN2 gene is an excellent therapeutic target because it has the potential to produce normal SMN protein. However, due to a process called RNA splicing, a very small, but very important, piece of the SMN2 gene is not made into protein. Briefly, the DNA that encodes the SMN2 gene produces a pre-mRNA transcript. This is essentially an exact duplicate of the DNA but has now been copied into a slightly different molecular form called RNA. RNA is what is used to make protein (DNA cannot be used for this process), however, only a small percentage of the actual pre-mRNA contains the information that is used in the production of a protein. As an example, this pre-mRNA could be equated to a book that has 20 chapters, however, the information that is important for a particular recipe is found in chapters 1, 4, 9, and 20, the remaining chapters are simply junk and can be discarded. This is essentially what happens in RNA splicing. The important regions that are the instructions for making a particular protein are encoded in “exons” and the sequences in between are called “introns.” The cell can find the exons, bring them together, and remove the intron sequences, forming an RNA that is ready to make a protein. Unfortunately, in the case of SMN2, there is a mistake that tells that cell to throw out the final “chapter” or specifically, exon 7. Dr. Krainer has previously very elegantly shown that the basis for this error in assembling the SMN RNA is due to a disruption in a binding site for a protein that tells the cell’s machinery to include exon 7 in the final RNA.
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FightSMA’s 2005 Annual conference was held in Washington, D.C for the second year in a row. Researchers from around the world were present. Families, friends and other members of the SMA Coalition joined together for SMA Day on the Hill. FightSMA families and members of the SMA Coalition traveled to the offices of Representatives and Senators to seek their support. Congressman Cantor has graciously hosted an evening reception on Capitol Hill.

The meetings in April opened the door to a deeper understanding of the disease and strengthened relationships within the SMA community. The following lay research summaries were prepared by Chris Lorson, PhD, FightSMA’s Science Director.
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Oxford BioMedica, the leading gene therapy company, announces today that they have received a Notice of Allowance from the US Patent Office for a Patent containing broad claims covering modifications to lentiviral vectors that improve safety and efficacy.

Oxford BioMedica owns an extensive portfolio of broad patents and patent applications covering many aspects of the composition of matter and use of gene delivery systems based on lentiviral vectors. This patent estate underpins the Company’s neurotherapy pipeline of five products and is the subject of recent commercial deals with a number of companies including Merck and Biogen Idec.
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New research suggests that an off-the-market pain reliever called indoprofen may be a starting point for finding a new drug to treat spinal muscular atrophy (SMA), a devastating childhood neurological disorder.

The discovery of the linkage between indoprofen and SMA resulted from the National Institute of Neurological Disorders and Stroke (NINDS)-sponsored Drug Screening Consortium, which screened a collection of 1040 clinically approved drugs for possible activity against amyotrophic lateral sclerosis and other neurodegenerative disorders in 2001 and 2002.
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Trophos, a biopharmaceutical company based in Marseille, France, and dedicated to the discovery and development of drugs for chronic neurodegenerative diseases, announced today the initiation of a Phase I clinical trial for its lead compound TRO19622, an investigational drug to treat neurodegenerative disorders, with a first application to Amyotrophic Lateral Sclerosis (ALS) and Spinal Muscular Atrophy (SMA) patients.

The clinical trial will take place in France and will include both a single dose study and a multiple dose study on healthy adult subjects. Its purpose is to evaluate the safety and tolerability of TRO19622. The company expects that this trial will be completed at the end of the third quarter of 2005. TRO19622 is expected to prevent the release of apoptotic factors from mitochondria, and therefore protect the neuron.
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One of the best parts of coming to the FSMA conference is the chance for SMA families and adults with SMA to interact with the researchers who are trying to find a treatment or cure. This year over 100 researchers and clinicians from all over the world attended the FSMA Scientific Conference which was held concurrently with the Family conference. While these researchers and clinicians meet separately from the families, they are involved in many other parts of the conference. The following is the text of Sunday morning’s session, which followed the Awards Brunch where the 22 chapters, 6 international affiliates, members of the International Alliance for SMA, and many individuals were honored for their fundraising efforts. Dr. Chris Spancake, FSMA Director of Research, made some introductory remarks, then Dr. Arthur Burghes and Dr. Kathy Swoboda spoke, and then the floor was opened for questions for about two hours. This is a transcription of the updates and questions and answers.
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Families of Spinal Muscular Atrophy (FSMA), an organization founded to promote research leading to effective treatment of Spinal Muscular Atrophy (SMA), a debilitating and often fatal disease, today announced the next step in its partnership with deCODE genetics. FSMA and deCODE are making available deCODE’s high-throughput screening capabilities to test promising compounds that may increase SMN levels or supplement SMN function.

Using compounds identified through previous FSMA-funded research, deCODE’s Chicago-based pharmaceuticals group has completed initial screening and is now working to optimise hits to obtain the best activity and drug like properties. FSMA and deCODE are now hoping to collaborate with other parties in order to make available the necessary chemistry resources to progress other potentially effective compounds through the evaluation process. These services will be made available under the current collaboration that is being funded by FSMA. Read the rest of this entry »

Paratek Pharmaceuticals, Inc. and Families of Spinal Muscular Atrophy (FSMA), an organization founded to promote research leading to the effective treatment of Spinal Muscular Atrophy (SMA), a debilitating and often fatal disease, today announced an agreement to research Paratek’s novel small molecules as a possible treatment for SMA. Using a specific subset of Paratek’s novel compounds that were identified through a previous collaborative effort between researchers at the University of Massachusetts Medical School and Paratek Pharmaceuticals, investigators sponsored by Families of SMA will begin testing these compounds both in the laboratory and in animal models of SMA to evaluate their potential use in treating SMA. Read the rest of this entry »

Salt Lake City, UTAH and Libertyville, ILLINOIS September 16, 2003 — Families of Spinal Muscular Atrophy, the leading funder of Spinal Muscular Atrophy (SMA) research, today announced the launch of two breakthrough drug safety studies in children with SMA. These studies are the first two drugs going forward that have shown increase in SMN protein.

The two studies are drug safety studies that will examine the tolerability by SMA patients of medications currently available for treatment of other diseases and conditions. The studies, conducted by Dr. Kathryn Swoboda and her team at the University of Utah and Primary Children’s Medical Center, are being funded by Families of SMA’s Project Cure SMA. This is the first clinical study planned by the Project Cure SMA team, a collaborative effort of SMA clinicians worldwide. Read the rest of this entry »

deCODE genetics and Families of Spinal Muscular Atrophy (FSMA), an organization founded to promote research leading to the effective treatment of this debilitating and often fatal disease, today announced the signing of an agreement aimed at developing a new therapeutic compound for SMA. Using promising compounds identified through previous FSMA-funded gene- and drug-discovery work, deCODE’s Chicago-based pharmaceuticals group will identify the most promising lead compounds, optimize these compounds, and conduct the medicinal chemistry and scale-up work to develop a potentially effective new drug ready for clinical trials. The three-year agreement is potentially worth $5.2 million, including milestones for the successful development of a compound approved for clinical trials. FSMA will retain all rights to drugs developed under the alliance for use in treating SMA as well as royalties on sales for their use in other indications. Read the rest of this entry »

By Douglas Kerr, M.D., Ph.D., Assistant Professor, Neurology, Johns Hopkins Hospital

I have been asked to comment on the status of stem cells in motor neuron disease, specifically in spinal muscular atrophy. As some of you may know, I am a neurologist at Johns Hopkins Hospital. I see patients with spinal muscular atrophy and other motor neuron diseases. My research focuses on mechanisms of motor neuron degeneration and potential strategies for regeneration. Approximately two years ago I began looking at a potential role for neural stem cells in animal models of spinal muscular atrophy. 

So where are we with this potential strategy? The bottom line is that this is a potentially very exciting therapy and advances are being made rapidly. However, we still do not know the safety of this therapy and as a result we are still several years away from human trials.
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Objective: To determine whether thyrotropin-releasing hormone (TRH) can increase muscle strength in children with spinal muscular atrophy types 2 and 3.

Design: A randomized, double-blinded, controlled, 5-wk drug trial of six subjects and three controls. Subjects and controls ranged from 4 to 8 yr of age and were randomly assigned to treatment and placebo groups in a ratio of 2:1. TRH (protirelin) or placebo was delivered intravenously through percutaneous intravenous catheters at a dose of 0.1 mg/kg (in 50 ml of normal saline) for a total of 29 days. Patients were evaluated using electromyography and handheld dynamometry of the deltoids, biceps, triceps, wrist extensors, hip flexors, quadriceps, hamstrings, and grip strength before and immediately after 5 wk of treatment. A unidirectional t test was used to compare mean values.

Results: Dynamometry improved significantly only for the six treated subjects (P < 0.02). Peroneal nerve conduction velocities were significantly faster in the treatment group (paired t test, P = 0.036). The parents of the treated children also provided anecdotal evidence of improvements in function. Improvements lasted 6-12 mo.

Conclusions: TRH may be a useful treatment for spinal muscular atrophy. A larger, crossover design group comparison study is warranted.
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