Résumé :
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Spinal muscular atrophy (SMA), a recessive autosomal disorder, is one of the most common genetic causes of death in childhood. It is caused by mutations of the survival motor neuron (SMN) gene. We previously reported that Lentiviral vector expressing SMN was successfully used to increase the life expectancy by 5 days1. The marginal efficacy of this therapeutic approach, however, prompted us to explore different strategies for gene delivery to motor neurons to achieve a more clinically relevant result. The first part of this presentation will describe the efficiency of scAAV9 mediated SMN gene replacement in SMA mouse model. We report that a single systemic injection of SMN-expressing scAAV9 vector reversed the phenotype of SMN_7mice2, a well established animal model of SMA. Most notably, SMN replacement led to substantial increase in the life expectancy, thereby achieving one of the highest therapeutic effects reported in the field to date3. The second part will discuss the role of PTEN, a negative regulator of the target of rapamycin (mTOR) pathway, in SMA. AAV6 expressing siPTEN into hind limb muscles at postnatal day 1 in SMN_7 mice leads to significant PTEN depletion and robust improvement in motor neuron survival. These studies report promising advances in AAV-based therapy for SMA. We are currently planning to initiate clinical trials using scAAV-based SMN replacement in the very near future.References: 1. Azzouz et al. J. Clin. Inv. 114, 1726-1731 (2004). 2. Le et al. Hum Mol Genet 14, 845-857 (2005 ). 3. Valori et al. Sci. Transl. Med. 2, 35ra42 (2010).
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