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.

Keywords: Patisiran; RNAi; TTR amyloidosis; TTR gene; gene silencing; siRNA.

Figure 1

The RNAi mechanism is a powerful tool for gene silencing in mammalian cells. The siRNA pathway takes place as follows: (A) long dsRNA is cleaved by a member of RNAse III family, dicer, into around 21-nucleotide-long siRNAs. The siRNAs, generated either by (A) dicer cleavage or by (B) synthetic construction, are then introduced into cells, where they integrate into the RISC. Once unwound, the antisense strand of siRNA guides RISC to the mRNA containing its complementary sequence, which triggers the destruction of the target by the endonucleolytic cleavage. Springer Methods Mol Biol. RNAi-based functional pharmacogenomics. 2011;700:271–290, Tuzmen S, Tuzmen P, Arora S, Mousses S. Copyright 2011, with permission of Springer Nature. Abbreviations: RNAi, RNA interference; siRNA, small interfering RNA; dsRNA, double-stranded RNA; RISC, RNA-induced silencing complex.

Figure 2

(A) Cytogenetic locus of TTR gene. (B) The human TTR gene. Reprinted by permission from Macmillan Publishers Ltd: Lab Invest. Teng MH, Yin JY, Vidal R, et al. Amyloid and nonfibrillar deposits in mice transgenic for wild-type human transthyretin: a possible model for senile systemic amyloidosis. Lab Invest. 2001;81(3):385–396. Copyright 2001. (C) The human TTR protein structure; adapted from RCSB PDB https://www.rcsb.org/pdb/explore/remediatedSequence.do?structureId=5TZL of PDB ID 5TZL. Kabsch W, Sander C. (1983) Dictionary of protein secondary structure: pattern recognition of hydrogen-bonded and geometrical features. Biopolymers. 22(12); 2577–2637. Abbreviations: DSSP, database of secondary structure proteins; Ex, exon; GP, general promoter; LSE, liver specific enhancer; PDB, protein databank; TSR, tissue specific regulator; TTR, transthyretin.

Figure 3

Mutations described in TTR gene. ATTR is caused by mutations in TTR gene the protein product of which is expressed mainly in the liver. There exist more than 100 mutations in TTR protein. From Alnylam Pharmaceuticals, Inc. Alnylam Pharmaceuticals discontinues revusiran development. 2016. Available from: http://investors.alnylam.com/releasedetail.cfm?ReleaseID=992320; with permission. Abbreviations: TTR, transthyretin; ATTR, TTR amyloidosis.