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Published on: May 12, 2013
Silencing mutant SOD1 using RNAi protects against neurodegeneration and extends survival in an ALS model
G Scott Ralph1, Pippa A Radcliffe, Denise M Day
1Oxford Biomedica Ltd, Medawar Centre, The Oxford Science Park, Oxford, OX4 4GA, UK. s.ralph@oxfordbiomedica.co.uk
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.
Insights
Gene silencing using RNA interference (RNAi) effectively reduced SOD1 expression in a mouse model of Amyotrophic Lateral Sclerosis (ALS). This groundbreaking therapy significantly delayed disease onset and extended survival in the SOD1 mice.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron death.
- Dominant mutations in the superoxide dismutase (SOD1) gene cause some familial ALS cases.
- RNA interference (RNAi) offers potential for targeted gene silencing in dominant genetic disorders.
Purpose of the Study:
- To investigate the therapeutic potential of RNA interference (RNAi) for silencing the SOD1 gene in a mouse model of ALS.
- To assess the impact of SOD1 gene silencing on motor neuron survival, disease onset, and lifespan in SOD1(G93A) mice.
Main Methods:
- Development of a lentiviral vector for expressing RNAi targeting the human SOD1 gene.
- Intramuscular injection of the lentiviral vector into SOD1(G93A) mice.
- Evaluation of SOD1 expression levels, motor neuron survival, motor function, and survival rates.
Main Results:
- Efficient and specific reduction of SOD1 expression was achieved in the targeted muscle groups.
- Improved survival of motor neurons in the brainstem and spinal cord was observed.
- Significant delay in the onset of ALS symptoms (over 100%) and extended lifespan (nearly 80%) were demonstrated.
Conclusions:
- RNAi-mediated SOD1 gene silencing is a promising therapeutic strategy for ALS.
- This study provides the first evidence of substantial survival extension in a dominant neurodegenerative disease model using RNAi.
- The achieved therapeutic efficacy represents a significant advancement in the field of ALS treatment.
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