Abstract
Small interference RNA (siRNA) is a double-stranded RNA of 21~25 nucleotides. siRNA functions using a natural phenomenon known as RNA interference (RNAi), a gene silencing mechanism. Hypothetically, siRNA can target and regulate the expression of any disease-related gene in a sequence-specific manner. In 1993, this mechanism was noticed in a nematode Caenorhabditis elegans, later discovered in humans. After two decades, in 2018, the first siRNA therapeutics (Patisiran) were developed successfully and got approval from USFDA. Followed by three more siRNA drugs (Givosiran, Lumasiran, and Inclisiran) approved in consecutive years to treat rare, inherited genetic disorders. Recently approved one is Vutisiran with a similar indication of patisiran. Limitation of conventional therapies, this new & standard pharmacotherapy opens a new era of changing the treatment options of human diseases. Six siRNA candidates are in phase III clinical trials and are hoped to enter the pharmaceutical market soon. Challenges faced during the development of these novel therapies were off-target effects, target-specific delivery, cellular uptake, recognition by the innate immune system, limited efficacy, and others. However, chemical modification of the siRNA nucleotides in sugar, base, and phosphate moiety makes it successful in overcoming obstacles. In addition, a non-viral delivery carrier also helped in many aspects during formulation. This study is a narrative review and will summarize pharmacokinetic, pharmacodynamic, design approaches, and other attributes faced during the development of marketed siRNA products.
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