Grant: Operating Grant

Spinal muscular atrophy (SMA) is a devastating disorder primarily affecting newborns and young children. It is caused by reduced levels of the survival motor neuron (SMN) protein. Although normally expressed in all cells of the body, reduced expression of SMN results in degeneration of motor neurons, leading to muscle weakness and, in the case of severe disease, death. Currently, there is no effective treatment or cure. Our studies have uncovered that a small proportion of SMN is naturally released by cells in small vesicles called exosomes. Exosomes are normally involved in cell-to-cell communication, so exosomes released from one cell can be taken up by other cells elsewhere in the body. This raises the possibility of developing SMN-containing exosomes as a therapy to deliver the protein to deficient cells. In our first approach, we will use cells in culture to produce the therapeutic SMN-containing exosomes, and examine the efficiency with which they deliver the protein to SMN-deficient cells in culture and in a mouse model of SMA. In our second approach, we will deliver a virus containing a good copy of the SMN gene to the liver of mice, such that the exosomes naturally produced by the liver will have enhanced levels of SMN for delivery throughout the body. We will determine if this latter approach can lead to disease correction and extension of lifespan in the mouse model of SMA. Achieving our research goals will provide an effective therapy for patients afflicted with SMA.