Update on the clinical utility of an RNA interference-based treatment: focus on Patisiran

Abstract

RNA interference (RNAi) is a naturally existing endogenous mechanism for post-transcriptional gene regulation, nowadays commonly utilized for functional characterization of genes and development of potential treatment strategies for diseases. RNAi-based studies for therapy, after being examined for over a decade, are finally in the pipeline for developing a potential treatment for the mutated transthyretin (TTR) gene, which gives rise to a dysfunctional TTR protein. This dysfunctional protein causes TTR amyloidosis (ATTR), an inherited, progressively incapacitating, and often fatal genetic disorder. TTR is a protein produced in the liver, and functions as a carrier for retinol-binding protein and also thyroxine. This protein facilitates the transport of vitamin A around the human body. A mutation or misprint in the code of this protein results in an abnormal folding of the protein. Therefore, not only does the transportation of the vitamin A become disabled, but also there will be formation of clusters called amyloid deposits, which attack the heart and the nerves causing some patients to be unconditionally bound to bed. ATTR is a hereditary autosomal dominant disease with a 50% chance of inheritance by offspring, even with just one of the parents having a single defective allele of this gene. Alnylam Pharmaceuticals worked on the concept of RNAi therapy for years, which led to the introduction of lipid nanoparticles encircling small interfering RNAs. The drug showed extremely positive results since the first trial, and a great percentage of defective protein reduction. This drug was later named Patisiran.

Nanoparticles Containing Oxidized Cholesterol Deliver mRNA to the Liver Microenvironment at Clinically Relevant Doses

“…Systemic delivery of therapeutic RNA to hepatocytes has led to an FDA approved drug [21] . Delivery to non-hepatocytes has remained more challenging.…”

Systemic Delivery of Small Interfering RNA Therapeutics: Obstacles and Advances

“…Cancer cells have been reported to overexpress VEGF; hence, siRNA drug targeting inhibition of this gene has notably demonstrated anticancerous activity with sufficient tolerance to the drug (Fitzgerald et al, 2017). Mutation in the transthyretin (TTR) gene results in elevated levels of amyloid and accumulation of these fibrils in various tissues results in heart failure, central nervous system breakdown, and postural hypotension (Rizk and Tüzmen, 2017). This drug already passed the clinical evaluation and approved by FDA as already mentioned in this review.…”

Delivery of mRNA Therapeutics for the Treatment of Hepatic Diseases

“…Together with the approval of Patisiran, which is an LNP-delivering siRNA, these data give evidence for the controllability of immunogenicity and safety concerns. 73…”