T.O.5 Spinal muscular atrophy SMA: SMNs spatial requirement and therapies

Abstract SMN is expressed in all tissues but its deficiency in SMA selectively affects neurons. Using mice that model severe SMA we have tested whether SMN needs to be replaced in all tissues. Furthermore we have used antisense morpholinos (ASO) directed against ISS-N1 delivered to the nervous system to correct SMA mice. Using mice lines that can either remove mouse SMN expression or restore mouse SMN expression when Cre is expressed we have determined the spatial requirement for SMN in SMA. Removal of SMN from neurons to create SMA neurons in the background of all other cells with normal SMN results in mice with a severe phenotype likewise restoration of SMN to neurons with all other tissues remaining at low levels results in correction. While the Cre drivers clearly indicate that motor neurons are one of the critical neural types for SMN restoration it is not the only neuronal type that requires high SMN levels. Furthermore we have knockdown SMN in pig motor neurons and other neuronal populations in the pig using intrathecal delivery of AAV9-shRNA this resulted in a clear SMA like phenotype. Furthermore with efficient transduction of motor neurons the cell bodies of the motor neuron where retained but ventral root axons showed a marked loss indicating that reduction in SMN results in motor axonal problems prior to the cell body. In mice the intracerebralventricular delivery of ASO has a marked impact on SMA mice we are now investigating the distribution of ASO after intrathecal or ICV delivery initial results indicate it is possible to obtain wide distribution in the nervous system of both adult and neonatal animals.