Somatic therapy of a mouse SMA model with a U7 snRNA gene correcting SMN2 splicing

Odermatt, Philipp; Trüb, Judith; Furrer, Lavinia; Fricker, Roger; Marti, Andreas; Schümperli, Daniel (2016). Somatic therapy of a mouse SMA model with a U7 snRNA gene correcting SMN2 splicing. Molecular therapy, 24(10), pp. 1797-1805. Nature Publishing Group 10.1038/mt.2016.152

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Spinal Muscular Atrophy (SMA) is due to the loss of SMN1 gene function. The duplicate gene SMN2 produces some, but not enough, SMN protein because most transcripts lack exon 7. Thus, promoting the inclusion of this exon is a therapeutic option. We show that a somatic gene therapy using the gene for a modified U7 RNA which stimulates this splicing has a profound and persistent therapeutic effect on the phenotype of a severe SMA mouse model. To this end, the U7 gene and vector and the production of pure, highly concentrated self-complementary (sc) AAV9 vector particles were optimized. Introduction of the functional vector into motoneurons of newborn SMA mice by intracerebroventricular injection led to a highly significant, dose-dependent increase in life span and improvement of muscle functions. Besides the central nervous system, the therapeutic U7 RNA is expressed in the heart and liver which may additionally contribute to the observed therapeutic efficacy. This approach provides an additional therapeutic option for SMA and could also be adapted to treat other diseases of the central nervous systems with regulatory small RNA genes.

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