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.
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Other articles about this breakthrough:

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

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.

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

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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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