Silencing SOD1 for Mutant Huntingtin Through RNA Interference Results in Neuroprotective Effects
Abstracts & Commentary
Commentary by M. Flint Beal, MD, Professor and Chairman, Department of Neurology, Cornell University Medical College, New York, NY, and Editor of Neurology Alert.
Synopsis: In SOD1(G93A) transgenic mice, a model for familial ALS, intraspinal injection of a lentiviral vector that produces RNAi-mediated silencing of SOD1 substantially retards both the onset and the progression rate of the disease.
Sources: Ralph GS, et al. Silencing Mutant SOD1 Using RNAi Protects Against Neurodegeneration and Extends Survival in an ALS Model. Nature Medicine. 2005;11:429-433; Raoul C, et al. Lentiviral-Mediated Silencing of SOD1 Through RNA Interference Retards Disease Onset and Progression in a Mouse Model of ALS. Nature Medicine. 2005;11:423-428; Harper S, et al. RNA Interference Improves Motor and Neuropathological Abnormalities in a Huntington’s Disease Mouse Model. Proc Natl Acad Sci. 2005;102:5820-5825.
RNA interference (RNAi) is an evolutionarily conserved post-transcriptional mechanism of gene silencing. RNAi is mediated by small interfering RNA consisting of 19-23 nucleotides of double-stranded RNA duplexes. They hybridize with mRNA targets and then promote specific endonucleolytic cleavage through an RNA-induced silencing complex. Long-lasting RNAi based gene therapy can be achieved using lentiviral based expression systems.
Such an approach was recently utilized in a transgenic mouse model of ALS. These are mice which have the G93A mutation in SOD1. They typically develop a progressive loss of motor neurons and premature death. In 1 study, RNAi was injected intraspinally. This produced a substantial retardation of both the onset and the progression of the illness. There was also improved survival of motor neurons.
In a second study, more impressive results were obtained. In this study, Raoul and colleagues generated a lentiviral vector to mediate expression of RNAi molecules specifically targeting the human SOD1 gene. This vector was then injected into various muscle groups of the mice. It resulted in efficient and specific reduction in SOD1 expression. There was improved survival of vulnerable motor neurons in both the brain stem and the spinal cord. There was a marked improvement in motor performance. Furthermore, there was a marked delay in the onset of ALS symptoms by more than 100%, and an extension in survival by nearly 80% of the normal lifespan. This is the most impressive result in showing a neuroprotective effect achieved in these mice to date.
The approach of using RNAi may also be useful in autosomal dominant diseases such as Huntington’s disease. The therapeutic promise of potentially silencing the mutant huntingtin was shown when symptoms were reversed when mutant huntingtin expression was turned off in a tetracycline regulated mouse model.
In a new study, a transgenic mouse model of Huntington’s disease was injected with RNAi using an adeno-associated viral vector. The results showed that the siRNA construct reduced human huntingtin expression in vitro. It also reduced the expression in the transgenic huntingtin mice. Stride length and motor behavior was improved in mice, which were injected bilaterally into the striatum. The vector eliminated the accumulation of huntingtin reactive neuronal inclusions. There was reduced mutant disease causing human huntingtin transgene, but it had no effect on normal mouse huntingtin expression, because of sequence differences between the mouse and human genes.
Commentary
These 2 studies show that the approach of using RNAi to silence mutant genes may have great promise. The study in the ALS transgenic mouse model showed the best improvement in survival yet achieved in these mice. One worry is that inactivating the normal copy of SOD could have deleterious effects. One strategy, which may be utilized, is also to place a normal copy of the gene in the lentiviral vector, which has been engineered so that it cannot be inactivated by RNAi. This will prevent any detrimental consequences of loss of the wild-type gene. Similarly, an siRNA showed both behavioral and neuropathologic benefits in the mouse model of HD. These 2 studies, therefore, show the feasibility of treating either ALS associated with mutant SOD1 or HD by directly reducing the expression of the genes using RNAi. Such an approach may have general applicability to treating dominant neurodegenerative disorders.
In SOD1(G93A) transgenic mice, a model for familial ALS, intraspinal injection of a lentiviral vector that produces RNAi-mediated silencing of SOD1 substantially retards both the onset and the progression rate of the disease.
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