SMA Research

Following is an abbreviated time-line list of the current and on-going research in the race for the cure for SMA

  • January 31, 2000:     Medical researchers announced a critical break through in the understanding of Spinal Muscular Atrophy, that may lead to a cure for the disease!  Researchers replicated the disease in mice and demonstrated that SMA could be corrected by large amounts of the SMN2 protein.  This may help to reduce the effects of this devastating disease, and be able to reverse the impact of SMA!

  • March 2000:     Researchers announce SMA Mouse Model.  This mouse model will allow researchers to continue to study SMA at a molecular level.  It will also be used to identify and test therapeutic strategies and the effectiveness of compounds discovered in the high-throughput drug screening.

  • August 2000:    There has now been an identification of the first factor (or protein) capable of making the SMN2 gene produce a much larger quantity of the correct protein - 80% (instead of 30%) of what the SMN1 gene should be producing.   This factor is called Htra2-ß1.   This factor has, so far, only been tested in a cell culture, but it should be suitable for testing in the genetically engineered SMA mice. That step is underway.

  • November, 2000:     Scientists at Johns Hopkins report restored movement to newly paralyzed rodents by injecting stem cells into the animals' spinal fluid!  "This research may lead most immediately to improved treatments for patients with paralyzing motor neuron diseases, such as SMA."  Jeffrey Rothstein, M.D., PhD.

  • December 2000:    Aurora is performing initial drug screens using various systems and have Identified compounds that DO appear to increase the amount of SMN!  These are Primary Hits which need to be further explored.

  • May 2001:    A Recent study uncovers signs that Folic Acid and B12 may lessen some ill effects of SMA!

  • November 2001:   Recently, information has been published on research conducted in Taiwan regarding the potential use of sodium butyrate for treating spinal muscular atrophy!

  • May 2002:    A treatment has been found to restore SMN2 levels to cells from Type 1 SMA Patients!  It is called Aclarubicin.

  • January 22, 2003:  Canadian Scientists Make Spinal Muscular Atrophy Breakthrough.  Study could lead to new therapy for devastating childhood disease.  

    OTTAWA, January 22, 2003 — Scientists at the Ottawa Health Research Institute have achieved a gene therapy breakthrough that could lead to the first effective treatment for spinal muscular atrophy -- the leading genetic killer of infants.  Spinal muscular atrophy, or SMA, destroys nerve cells that control muscle movements such as crawling, walking, swallowing and breathing. The disease strikes one in every 6,000 live births. SMA is usually diagnosed in babies under 18 months old, but certain types of the disorder can appear in later life. Babies born with the disease usually die of paralysis and respiratory failure before their second birthday.  SMA is caused by mutations in a gene that produces a crucial protein called survivor motor neuron, or SMN. Without sufficient amounts of this protein, nerve cells that control muscles and breathing degenerate and die.  "Children born with the most severe form of the disease will never be able to sit up. They'll look floppy. They may not show any expression in their face because the cranial nerve that controls smiling might be affected," says Dr. Christine DiDonato, Senior Research Associate at the OHRI.  In a study published in the current issue of Human Gene Therapy, Dr. DiDonato, along with virologist Dr. Robin Parks and molecular biologist Dr. Rashmi Kothary, both scientists at the OHRI and professors at the University of Ottawa, used a disabled adenovirus, a harmless virus, to deliver a healthy copy of the SMN1 gene into human cells.  The team used skin cells taken from patients with spinal muscular atrophy because they are easier to grow than motor neurons and show the same effects of SMA. Healthy human cells contain small cell structures called "gems", areas rich in SMN that look like star bursts. Cells from people with spinal muscular atrophy contain few gems, or none at all. Dr. DiDonato and her colleagues showed that by infecting the cells with an adenovirus carrying the SMN1 gene, they could make more gems appear.  The next stage is to move into animal models of the disease. But the early success is a promising step toward an eventual gene therapy treatment for SMA, Dr. DiDonato says.  The team's research was funded by the Canadian Institutes for Health Research, the Muscular Dystrophy Association and Families of Spinal Muscular Atrophy.  The Ottawa Health Research Institute  The OHRI is the research arm of The Ottawa Hospital, and a major part of the University of Ottawa Faculty of Medicine and Faculty of Health Sciences. Its research programs are grouped into: Molecular Medicine, Cancer Therapeutics, Clinical Epidemiology, Diseases of Aging, Hormones, Growth and Development, Neuroscience, and Vision. With over 100 scientists, 225 students and 400 support staff, and $34 million in external funding, the OHRI is one of the fastest growing, and most respected hospital-based research institutes in Canada.

  • May 16-17, 2003:  SMA colloquium,  Association Française Contre les Myopathies (AFM), Evry, France May 16 : Diagnosis-Genetics-Pathology The first day of the colloquium was dedicated to recent developments in fundamental and pre-clinical research, as well as clinical and genetic diagnosis of spinal muscular atrophy. Several hundred people attended the meeting. Ketty Schwartz (President of the Scientific Council of AFM) gave an introduction. Simultaneous translation was available, providing French translation of the English lectures and vice-versa. The day consisted of five plenary sessions, each followed by discussion. Highlights are summarized below. Notably, several projects are supported by international co-financing. Examples of some sponsors are AFM, Families of SMA, and Andrew´s Buddies. 1. Clinical and genetic diagnosis: recent progress An overview was presented of the clinical characteristics of infantile SMA. The relative frequencies of various forms of SMA were shown, including those not due to SMN mutations (<10%). The diagnosis of proximal SMA is essentially clinical, and may be confirmed by genetic testing. (Dr. Louis Viollet, AFM, Evry, France)  Genetic counseling for SMA is a complex issue. The molecular mechanisms of the disease generate both deletions and duplications, and the duplications may mask the deletions. Not all morbid alleles are detectable at present, and the cis/trans relationship of multiple copies of SMN1 and SMN2 cannot yet be determined. Therefore a residual risk always remains.  It was suggested that a search for heterozygous deletion of SMN1 is not indicated when the a priori risk is equal to or lower than 1/2560. A special concern in prenatal diagnosis is whether or not to disclose heterozygous status of a fetus to the parents. Dr. K. Fischbeck (NINDS, U.S.A.) raised the question of whether broader screening should be applied. The speaker replied that cost is not an issue. (P.Saugier-Veber e.a., CHU de Rouen, France)   There is a rough correlation between the number of copies of SMN2 and severity of disease, but this is only valid for extreme phenotypes, and exceptions exist. The level of complete RNA and protein has a better correlation to  disease severity. This research group is interested in studying the genotype and phenotype of SMA type IV. (V. Cusin, Dijon, France)   2. Cellular and murine models  The biochemistry and physiology of SMN protein was presented in detail. The function of SMN seems to be the selection of correct RNA. In a complex with other proteins, SMN functions as a specificity factor essential for the efficient assembly of SM proteins on U snRNAs. This process probably protects cells from potentially harmful, non-specific binding of Sm proteins to RNA. Using a chicken cell-line knocked out for SMN and transfected with SMN under a tetracycline promoter, high throughput screening has been performed on compounds which already have FDA approval and/or can be categorized as vitamins. Specificity was improved by excluding compounds which enhanced the transcription of another gene under control of the tetracycline promoter. About half of the reactive compounds were thus eliminated. Twenty to 30 compounds remain, and can be categorized to two structural classes. Since the levels of SMN are not directly raised, the compounds evidently help the SMN complex in its function. The compounds tested are pharmacologically favorable, and information is available about them. The speaker hinted that SMA patients would do well to avoid sub-optimal doses of folic acid. In response to a direct question, he said that folic acid had not been tested. (G. Dreyfuss, University of Pennsylvania, U.S.A.).   Observations on existing and novel models of SMN conditional knock out mice show that reduced SMN expression in satellite cells has a strong effect on disease severity. (J. Melki et al., INSERM/University of Evry, France)  A model was presented for learning about the function of the various SMN domains and the subnuclear distribution of SMN. Green fluorescent protein was fused to various domain-deletion mutants and expressed in COS cells. (S. Lefebvre, Inst. Jacques Monod, Paris, France)   3. Therapeutic strategies for SMA To develop therapeutic strategies aimed at increasing SMN levels it is important to understand whether overexpression of SMN or SMN ?7 is toxic, where high levels of SMN are required for correction of SMA and when SMN levels need to be restored. Mouse models have shown that high levels of SMN are not detrimental and that increased expression of SMN?7 makes the severe phenotype milder. Correction of SMN levels in muscle or nervous tissue alone is not sufficient to correct the SMA phenotype, and experiments are in progress to study the effect of simultaneous correction in both tissues. A model in zebrafish may provide information about the function of SMN in correct axonal pathfinding of motor neurons.  Screening for therapeutic compounds was started by Aurora Biosciences and is now being done by Vertex Pharmaceuticals. Aclarubicine has an effect but is toxic. A splicing screen did not produce any leads. Analysis of relevant promoters has yielded 29 compounds, which fall into 9 chemical classes. The next talk highlights findings on valproic acid. (A. Burghes et al., Ohio State University, U.S.A.)  Valproic acid is an approved drug with histone deacetylase (HDAC) inhibitor acitivity. It significantly increases exon 7-containing SMN mRNA transcripts and protein levels in fibroblast cell lines derived from SMA type 1 patients. Addition of VPA increased the number of gems (the intra-nuclear structures which contain SMN). VPA was shown to both promote correct splicing of SMN2 and to activiate the SMN promoter. VPA has a different mechanism of action than phenyl butyrate. VPA and related compounds should be studied further as potential drugs for treating SMA (C.Sumner, H. Thanh et al., NINDS, Bethesda, U.S.A.)   A study of 4-phenyl butyrate (PBA) has been started on 80 patients with SMA type II or III. Parameters studied include Hammersmith motor ability score, myometry, and forced vital capacity. (C. Brahe, Univ. Cattolica S. Cuore, Rome, Italy)   One approach to developing intervention in the SMA disease process is to prevent the cascade of events that lead from reduced levels of SMN protein to motorneuron degeneration and death. This approach is being explored by the drug-discovery start-up company Trophos. Purified motor motorneurons are seeded using robots in multi-well plates and induced to die, either by removing neurotrophic factors or by exposing them to high levels of excitatory amino acids. At the same time single compounds from the Trophos chemical library are added and assayed for their ability to prevent this cell death. Promising compounds are analyzed further, and finally tested in animal models. Several compounds are still in the running. It is likely that a successful therapy will require intervention at more than one level. (Henderson et al., INSERM-IDBM, Marseille, France)   4. Cellular therapy Mice were developed with a deletion in murine SMN exon 7 (SMN ?7) localized either to mature muscle cells (fused myotubes) or to mature muscle cells together with muscle progenitor cells (satellite cells). The second group of mice develop severe disease. In contrast, when the satellite cells are heterozygous for full length SMN and SMN ?7, disease is much milder and survival is longer. The author suggests that muscle progenitor cells might thus be a rational therapeutic strategy for myopathies. (S. Nicole, J. Melki et al., INSERM/University of Evry, France).   Stem cells have been used to treat animals with experimental spinal cord injury. Furthermore, research is proceeding on the differentiation of embryonic stem cells into motorneurons in vitro. So far, motorneuron-differentiated ES cells fail to traverse white matter, likely due to myelin-mediated axonal repulsion. This can be partially overcome with the addition of the compound Y-27632. Studies are underway on motorneuron-differentiated ES cells derived from  SMA and SOD1-G93A (a model for familial ALS) mice. (D. Kerr, Johns Hopkins Hospital, Baltimore, U.S.A.)   5. Gene therapy One line of experimental gene therapy is intra-muscular injection of adenoviral vectors coding for neurotrophic factors. This was done in several mouse models for motor neuron diseases. Another possibility is to use naked plasmid vectors combined with electroporation (a method based on the application of controlled electrical impulses). This is also  being tried in mice. (J. Lesbordes, Inst. Cochin de  génétique moléculaire, Paris, France)   Gene therapy approaches using the lentivirus EIAV (equine infectious
    anaemia virus) may offer a promising strategy for the delivery of genes into motor neurons via peripheral administration at the muscle. This concept is being explored in a mouse models for SMA. EIAV gene transfer in a mouse model for type I SMA leads to widespread expression of the transgene, extending the survival of these mice. Type III SMA mice intramuscularly injected with the vector showed increased long term expression of SMN in spinal motor neurons. Further work is going on to optimise the distribution of the SMN expressing lentiviral vectors and the survival of the treated mice. (M. Azzouz et al. Oxford Biomedica Ltd., Oxford, United Kingdom)   An important question which remains unanswered is why perturbations of SMN expression result in neuron pathology. SMN may play a role in the assembly of RNP complexes that are actively transported in neuronal processes. Studying cell lines with immunofluorescence and electron microscopic methods, SMN can be localized to subcellular structures. Live cell imaging showed the speed and direction of the movement of granules containing SMN. In contrast, SMN ?7 resulted in abnormal distribution of SMN. Exon 7 fused to DBF1 (a nuclear, DNA binding protein) targeted DBF1 to the cell cytoplasm. Overexpression of SMN ?7 resulted in a reduction in neurite length, and this could be overcome by fusing SMN ?7 to a targeting sequence which, in another system, is specific for axonal growth cones. The findings suggest that a novel function of SMN might be in trafficking of RNP complexes important for axonal growth or maintainance.  (G. Bassel, Albert Einstein College of Medicine, New York, U.S.A.)  Taija Heinonen

  • June 27, 2003:  Stem Cells Might Help in ALS and SMA in Unexpected Way  A study out today establishes that human stem cells can partly reverse a paralyzing neurological disease in rats — apparently without producing new nerve cells. The research, which generated headlines when it began several years ago, offers hope that stem cell therapy will work against paralyzing human diseases like amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA).  A team led by Jeffrey Rothstein, co-director of the Muscular Dystrophy Association’s ALS Center at Johns Hopkins University in Baltimore, first reported the experiments at a scientific conference in 2000. Then, it was believed that stem cells — master cells that build tissues such as nerve and muscle — might replace cells lost to disease, but it now appears they’re better at repairing damaged cells.  Rothstein and his group injected human primordial germ cells (which can morph into any cell in the body) into the spinal cords of rats infected with Sindbis virus. The virus is harmless to humans, but kills motor neurons (muscle-controlling nerve cells) connected to the rats’ hind limb muscles.  After 12 weeks, the treated rats had recovered some movement, and their hind limbs were 40 percent stronger compared to those of rats that had received “sham” injections without stem cells.  Examining the rats’ spinal cords, the researchers found that many of the injected cells had taken up residence there, but surprisingly few of the cells had become motor neurons. Further experiments showed that the stem cells release transforming growth factor-alpha (TGF-alpha) and brain-derived neurotrophic factor (BDNF) -- proteins that enhance neuronal survival and growth — and that blocking these proteins eliminated the stem cells’ beneficial effects.  The research appears in the current issue of the Journal of Neuroscience.   “In some ways our results reduce stem cells to the nonglamorous role of protein factories, but the cells still do some amazing, glamorous things we can’t explain,” said Hopkins researcher Douglas Kerr, in a statement issued by the university.  Human trials of stem cell therapy for ALS and SMA, which destroy motor neurons on a devastating scale, are still years away, the group says. But in preparation, they’ve begun testing stem cells in monkeys with motor neuron disease, and they’ve engineered rats with mutations in SOD1, a gene linked to about 2 percent of ALS cases.

  • Aug. 9, 2003:  Institute of Human Genetics University of Cologne, has confirmed valproic acid (VPA) as an important drug that restores the splicing pattern of exon 7 of SMN2 and activates the transcription of SMN2.  


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