Alzheimer’s disease (AD) is one of the most common forms of dementia. Existing therapeutics in AD are devoted to symptomatic relief. However, after the emergence of amyloid hypothesis, disease modifying therapeutics are being explored. According to amyloid hypothesis, a fundamental pathological event in AD is the sequential cleavage of the trans-membrane amyloid precursor protein (APP) by β-Site APP-Cleaving Enzyme1 (BACE1) and γ-secretase, generating toxic C-terminal fragments (CTF) and Amyloidβ (Aβ). Aβ deposition occurs in the extracellular space which leads to plaque formation.
The present work aims to inhibit the expression of gene responsible for production of BACE1 enzyme through RNA interference. RNA interference is an intracellular mechanism that can be used as a powerful tool for gene silencing mediated by small interfering RNAs (siRNA). Suitable siRNA is the critical factor for effective silencing which can be achieved by a design tool. A siRNA design tool was developed and its viability was established with the reported siRNA constructs for genes implicated in cancer. In AD, it is proposed to inhibit the cascade of reaction which is responsible for Aβ aggregation. The siRNA constructs generated were compared with validated datasets for BACE1. The results obtained for BACE1 were better in thermodynamic score, GC content, positional preferences as compared to validated datasets. The off-target silencing effects were also comparable with the published results. It is to be noted that the results generated are in silico and need to be verified on mammalian cell lines where BACE1 is expressed.
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