ABSTRACT
Systemic delivery of nucleic acids to the central nervous system (CNS) is a major challenge for the development of RNAinterference-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, weearlier demonstrated knockdown of target genes in the brain of both AbPP-PS1 (Alzheimer’s disease, AD) and wild-typeC57BL/6 mice. In this report, we further substantiate the approach through an extended use in AbPP-PS1 mice, which upontreatment with seven doses of b-secretase AbPP cleaving Enzyme 1 (BACE1) TARBP-BTP:siRNA, led to target-specificeffect in the mouse brain. Concomitant gene silencing of BACE1, and consequent reduction in plaque load in the cerebralcortex and hippocampus ([60%) in mice treated with TARBP-BTP:siRNA complex, led to improvement in spatial learningand memory. The study validates the efficiency of TARBP-BTP fusion protein as an efficient mediator of RNAi, givingconsiderable scope for future intervention in neurodegenerative disorders through the use of short nucleic acids as genespecific inhibitors.