Morpholino antisense oligomer against SOD1 for amyotrophic lateral sclerosis therapy

Neurotoxicity from accumulation of misfolded/mutant proteins is thought to drive pathogenesis in neurodegenerative diseases. Mutations in superoxide dismutase 1 (SOD1) are linked to familial amyotrophic lateral sclerosis (FALS) resulting in progressive motor neuron death through one or more acquired toxicities. Interestingly wild-type SOD1 has been associated also to sporadic ALS (SALS), as misfolded SOD1 has been reported in affected tissues of sporadic patients. For these reasons, it represents a promising therapeutic target for antisense oligonucleotides. We now report slowed disease progression, ameliorated neuromuscular function and increased survival in an ALS in vivo model following therapeutic delivery of morpholino (MO) oligonucleotides designed to reduce the synthesis of ALS-causing human SOD1. Neuropathological analysis demonstrated an increased motor neuron and axon number, an ameliorated muscle trophism and a reduced micro and macrogliosis-mediated inflammation. Moreover, MO yield robust SOD1 suppression, in particular of misfolded form, not only in vivo in ALS rodent, but also in human patient samples, setting the stage for MO-mediated therapy in human clinical trials.