Construct Modification that Limits the Neurotoxicity Caused by CNS-targeted RNAi
The significant neurotoxicity induced by RNAi constructs targeting HD gene expression was abrogated by using an miRNA delivery technique.
UIRF Case #:07083
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McBride JL, et al. Artificial miRNAs mitigate shRNA-mediated toxicity in the brain: implications for the therapeutic development of RNAi. Proc Natl Acad Sci U S A. 2008 Apr 15; 105(15): 5868-73.
Boudreau RL, Martins I, Davidson BL. Artificial microRNAs as siRNA shuttles: improved safety as compared to shRNAs in vitro and in vivo. Mol Ther. 2009 Jan; 17(1): 169-75.
Level of Development
General: in vitro
Researchers at the University of Iowa have found that the high levels of RNAi molecules used to curb expression of the HD gene cause neurotoxicity in models. Studies showed that the therapeutic affect against HD gene expression was not the source of the toxicity, because control missense RNAi molecules produced the same effect. These molecules, expressed in an shRNA construct produced high level of inhibitory RNA sequences, which is thought to be the source of the toxicity. The researchers, in response to this, created an miRNA-based construct, which produced substantially lower levels of the inhibitory molecules. Studies comparing the two methods paradoxically demonstrated near equal levels of HD gene expression inhibition, demonstrating that the new constructs were nearly equally as efficacious. These effects should benefit any RNAi construct targeted to the CNS.
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