Silencing mutant SOD1 using RNAi protects against neurodegeneration and extends survival in an ALS model

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease resulting in the selective death of motor neurons in the brain and spinal cord. Some familial cases of ALS are caused by dominant mutations in the gene encoding superoxide dismutase (SOD1). The emergence of interfering RNA (RNAi) for specific gene silencing could be therapeutically beneficial for the treatment of such dominantly inherited diseases. We generated a lentiviral vector to mediate expression of RNAi molecules specifically targeting the human SOD1 gene (SOD1). Injection of this vector into various muscle groups of mice engineered to overexpress a mutated form of human SOD1 (SOD1(G93A)) resulted in an efficient and specific reduction of SOD1 expression and improved survival of vulnerable motor neurons in the brainstem and spinal cord. Furthermore, SOD1 silencing mediated an improved motor performance in these animals, resulting in a considerable delay in the onset of ALS symptoms by more than 100% and an extension in survival by nearly 80% of their normal life span. These data are the first to show a substantial extension of survival in an animal model of a fatal, dominantly inherited neurodegenerative condition using RNAi and provide the highest therapeutic efficacy observed in this field to date.

Resveratrol Improves Motoneuron Function and Extends Survival in SOD1G93A ALS Mice

“…The beginning of symptoms for each animal was considered when it showed the first deficits in locomotor performance in the rotarod test [35]. Results revealed a significant delay of symptoms onset (Mantel-Cox test, p<0.05) in both female and male treated SOD1 G93A mice of 1 and 2 weeks, respectively, compared to untreated mice (Fig.…”

AAV-mediated gene therapy for retinal disorders: from mouse to man

“…AAV.shRNA delivery mediates improvements in motor neuron function and in neuronal morphology for at least 21 weeks in murine models of degeneration in the central nervous system. 56,57 Following studies showing that AAV.shRNA delivery reduces Rhodopsin expression in vitro, 58,59 a recent report shows that in vivo expression of a human Rhodopsin transgene can be reduced by up to 90% and that a nonsilenced Rhodopsin gene can be expressed to achieve a degree of rescue. Eyes treated with the suppression-replacement construct showed some preservation of photoreceptors, indicating this approach may be useful in treating dominantly inherited retinal degenerations.…”

RNAi: a potential therapy for the dominantly inherited nucleotide repeat diseases

“…48 Direct delivery of viruses expressing shRNAs can also be used for inhibition of gene expression 49,50 or disease targets. [51][52][53][54][55] Both a benefit and a concern from viralmediated delivery is that expression lasts from months to years. For a chronic neurogenetic disease, this would be ideal.…”