Delivery of BACE1 siRNA mediated by TARBP-BTP fusion protein reduces β-amyloid deposits in a transgenic mouse model of Alzheimer’s disease
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Systemic delivery of nucleic acids to the central nervous system (CNS) is a major challenge for the development of RNA interference-based therapeutics due to lack of stability, target specificity, non-permeability to the blood–brain barrier (BBB), and lack of suitable carriers. Using a designed bi-functional fusion protein TARBP-BTP in a complex with siRNA, we earlier demonstrated knockdown of target genes in the brain of both AβPP-PS1 (Alzheimer’s disease, AD) and wild-type C57BL/6 mice. In this report, we further substantiate the approach through an extended use in AβPP-PS1 mice, which upon treatment with seven doses of β-secretase AβPP cleaving Enzyme 1 (BACE1) TARBP-BTP:siRNA, led to target-specific effect in the mouse brain. Concomitant gene silencing of BACE1, and consequent reduction in plaque load in the cerebral cortex and hippocampus (>60%) in mice treated with TARBP-BTP:siRNA complex, led to improvement in spatial learning and memory. The study validates the efficiency of TARBP-BTP fusion protein as an efficient mediator of RNAi, giving considerable scope for future intervention in neurodegenerative disorders through the use of short nucleic acids as gene specific inhibitors.
KeywordsAlzheimer’s disease amyloid-β gene silencing peptide-based delivery system RNAi therapeutics siRNA delivery
The work was supported by BRNS (DAE) Grant No. 37(1)/14/51/2014-BRNS. The authors thank Mr Sairam for diligent help with animal dissections, and Ms Nandini Rangaraj for help with confocal microscopy. We acknowledge Ms Durga Jeyalakshmi Srinivasan’s inputs to the progress of this work, and timely assistance from Ms Haritha N with the in vivo experiments.
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