Titre :
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Development and preclinical evaluation of therapies for spinal muscular atrophy : Acte de colloque : 4ème colloque international de Myologie (9-13 mai 2011; Lille (France))
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contenu dans :
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Auteurs :
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Foust K ;
McGovern V ;
Poresnsky P ;
Bevan A ;
Duque S ;
Le T ;
Iyer C ;
Laporte A ;
Alwine I ;
Mitrpant C ;
Wilton S ;
Kaspar B
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Type de document :
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Article
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Editeur :
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AFM-TELETHON, 2011
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Pages :
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p. 16
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Langues:
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Anglais
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Mots-clés :
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adénovirus
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amyotrophie spinale
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colloque
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essai préclinique
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étude d'évaluation
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gène SMN1
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gène SMN2
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injection intrarachidienne
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jonction neuromusculaire
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morpholino
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oligonucléotide antisens
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phénotype
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protéine SMN
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souris modèle
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thérapie génique
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Résumé :
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Spinal muscular atrophy (SMA) is caused by loss of the SMN1 gene and retention of SMN2 which results in low SMN protein levels. We have mimicked this situation in mice creating mice with SMA. SMA mice can be corrected by expression of SMN in the nervous system but expression in muscle has no effect. Removal of functional Smn from muscle in the presence of SMN2 using Cre drivers results in no phenotype and replacement of Smn in muscle of SMA mice does afford any rescue. The data indicates that two copies of SMN2 provides sufficient SMN for most tissues and that nerve has a particular requirement for high SMN levels. We have also produced transgenes with inducible SMN these demonstrate that postnatal induction of SMN does rescue SMA mice but early induction is necessary for maximum affect. Furthermore removal of SMN induction later in life indicates two groups of animals those that die within a month and those that survive on their SMN2 neither group showing a marked motor neuron phenotype. This indicates that 2 copies of SMN2 produces SMN levels on the edge of what is required by all cells in adult live. We have investigated therapeutic approaches to SMA using drug compounds that induce SMN from SMN2, gene therapy using scAAV9 and antisense morpholino oligonucleotides (ASOs) directed against ISS-N1( intron splice silencer). To date drug compounds have shown minimal effect in SMA mice due to their limited ability to induce SMN, thus further drug compound development is required. Antisense morpholinos when given early into the neural system corrected splicing of SMN2, increased SMN levels and resulted in mice that survived for over 100days after a single dose of ASOs. We are investigating whether repeat dosing or delivery outside the nervous system is of further benefit. We have shown that scAAV9-SMN is highly effective at correcting SMA mice when given early with mice surviving over 300 days and possess a normal neuromuscular junction phenotype. In primates even of older age vascular delivery of scAAV9-GFP results in a remarkably efficient delivery of GFP to motor neurons and no marked toxicity. Indeed scAA9-SMN also showed no toxicity. Furthermore scAAV9-SMN can also be efficiently delivered to motor neurons by intrathecal injections in pigs. This sets the stage for clinical trials of scAAV9-SMN and ASOs in SMA.
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