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Thread: Follistatin

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    Chemistry Experiment heavyiron's Avatar
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    Default Follistatin

    INHIBITION OF MYOSTATIN WITH EMPHASIS ON FOLLISTATIN AS A THERAPY FOR MUSCLE DISEASE

    LOUISE R. RODINO-KLAPAC, PhD,1,2 AMANDA M. HAIDET, BS,1,2 JANAIAH KOTA, PhD,1,2 CHALONDA HANDY, BS,1,2 BRIAN K. KASPAR, PhD,1,2 and JERRY R. MENDELL, MD1,3

    1 Center for Gene Therapy, Research Institute at Nationwide Children's Hospital, 700 Children's Drive, Columbus, Ohio 43205 USA
    2 Department of Pediatrics, Ohio State University, Columbus, Ohio USA
    3 Department of Neurology, Ohio State University, Columbus, Ohio USA
    Correspondence to: J.R. Mendell; Email: [email protected]

    In most cases, pharmacologic strategies to treat genetic muscle disorders and certain acquired disorders, such as sporadic inclusion body myositis, have produced modest clinical benefits. In these conditions, inhibition of the myostatin pathway represents an alternative strategy to improve functional outcomes. Preclinical data that support this approach clearly demonstrate the potential for blocking the myostatin pathway. Follistatin has emerged as a powerful antagonist of myostatin that can increase muscle mass and strength. Follistatin was first isolated from the ovary and is known to suppress follicle-stimulating hormone. This raises concerns for potential adverse effects on the hypothalamic–pituitary–gonadal axis and possible reproductive capabilities. In this review we demonstrate a strategy to bypass off-target effects using an alternatively spliced cDNA of follistatin (FS344) delivered by adeno-associated virus (AAV) to muscle. The transgene product is a peptide of 315 amino acids that is secreted from the muscle and circulates in the serum, thus avoiding cell-surface binding sites. Using this approach our translational studies show increased muscle size and strength in species ranging from mice to monkeys. Adverse effects are avoided, and no organ system pathology or change in reproductive capabilities has been seen. These findings provide the impetus to move toward gene therapy clinical trials with delivery of AAV-FS344 to increase size and function of muscle in patients with neuromuscular disease.

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2717722/


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    Chemistry Experiment heavyiron's Avatar
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    Delivery of recombinant follistatin lessens disease severity in a mouse model of spinal muscular atrophy

    Ferrill F. Rose, Jr1,, Virginia B. Mattis2,, Hansjörg Rindt2, and Christian L. Lorson1,2,*

    1 Department of Molecular Microbiology and Immunology 2 Department of Veterinary Pathobiology, Life Sciences Center, Room 471G, University of Missouri, Columbia, MO 65211, USA
    * To whom correspondence should be addressed. Tel: +1 5738842219; Fax: +1 5738849395; Email: [email protected]
    Received August 22, 2008; Revised November 18, 2008; Accepted December 10, 2008

    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 on 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 an 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, when compared with 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.

    http://hmg.oxfordjournals.org/cgi/co...tract/18/6/997


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