Haroon Mohamed Mohamed, Saba Kamal, Boddedda Venkata Harshavardhan, Kumar Jerald Mahesh, Patel Anant Bahadur, Gopal Vijaya
CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500 007, India.
J Biosci. 2019 Mar;44(1).
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 (greater than 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.
由于缺乏稳定性、靶向特异性、血脑屏障（BBB）通透性差以及缺乏合适的载体，将核酸全身性递送至中枢神经系统（CNS）是基于RNA干扰的治疗药物开发面临的一项重大挑战。我们之前使用设计的双功能融合蛋白TARBP-BTP与siRNA形成复合物，证明了在AβPP-PS1（阿尔茨海默病，AD）小鼠和野生型C57BL/6小鼠的大脑中均可敲低靶基因。在本报告中，我们通过在AβPP-PS1小鼠中进一步广泛应用来证实该方法，用七剂β-分泌酶AβPP切割酶1（BACE1）TARBP-BTP:siRNA处理后，在小鼠大脑中产生了靶向特异性效应。在用TARBP-BTP:siRNA复合物处理的小鼠中，BACE1的基因沉默以及随之而来的大脑皮质和海马体中斑块负荷的降低（超过60%），导致空间学习和记忆能力得到改善。该研究验证了TARBP-BTP融合蛋白作为RNAi有效介导剂的效率，为未来通过使用短核酸作为基因特异性抑制剂干预神经退行性疾病提供了相当大的空间。
