Abstract
Neurotoxicity due to the accumulation of mutant proteins is thought to drive pathogenesis in neurodegenerative diseases. Mutations in superoxide dismutase 1 (SOD1) are linked to familial amyotrophic lateral sclerosis (fALS); these mutations result in progressive motor neuron death through one or more acquired toxicities. Interestingly, SOD1 is not only responsible for fALS but may also play a significant role in sporadic ALS; therefore, SOD1 represents a promising therapeutic target. Here, we report slowed disease progression, improved neuromuscular function, and increased survival in an in vivo ALS model following therapeutic delivery of morpholino oligonucleotides (MOs) designed to reduce the synthesis of human SOD1. Neuropathological analysis demonstrated increased motor neuron and axon numbers and a remarkable reduction in astrogliosis and microgliosis. To test this strategy in a human model, we treated human fALS induced pluripotent stem cell (iPSC)-derived motor neurons with MOs; these cells exhibited increased survival and reduced expression of apoptotic markers. Our data demonstrated the efficacy of MO-mediated therapy in mouse and human ALS models, setting the stage for human clinical trials.
Highlights
Mutant superoxide dismutase 1 (SOD1) protein induces a pathogenic phenotype when expressed in MNs16; it contributes to disease onset and early disease progression when it is expressed in microglia[16], astrocytes[15,17], and oligodendrocytes[18]
A scrambled morpholino oligomers (MOs) sequence was designed based on the best control sequence predicted by the bioinformatics tool (Gene Tools, www.genetools.com) and was used in all of the experiments as an internal control
We used western blot to demonstrate a slight decrease in SOD1 protein levels at all time points with MO1 and a significant reduction at all time points with MO2 (Supplementary Fig. 1A,B)
Summary
Mutant SOD1 protein induces a pathogenic phenotype when expressed in MNs16; it contributes to disease onset and early disease progression when it is expressed in microglia[16], astrocytes[15,17], and oligodendrocytes[18]. ASOs are nucleic acid analogs designed to trap RNAs by binding in a particular place and interfering with a specific biological process, such as splicing or translation[19] They represent a promising therapeutic strategy for the treatment of various human disorders and are currently being tested in clinical trials. Impressive therapeutic rescue has been observed using MOs in another genetic motor neuron disease, spinal muscular atrophy (SMA), which is caused by mutations in the survival motor neuron 1 gene[22,23,24] We confirmed this result by combining local and systemic administration of a 25-nt MO sequence (MO-10–34) in transgenic SMA mice. We investigated MO sequences targeting SOD1 in rodent and human fALS models and demonstrated their efficacy in significantly reducing SOD1 levels and in improving the disease phenotype
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