A Review of Patisiran (ONPATTRO®) for the Treatment of Polyneuropathy in People with Hereditary Transthyretin Amyloidosis

Abstract

Hereditary variant transthyretin amyloidosis (ATTRv) is a rare genetic defect that affects about 5000–10,000 people worldwide, causing amyloidosis secondary to misfolding of mutant transthyretin (TTR) protein fibrils. TTR mutations can cause protein deposits in many extracellular regions of organs, but those deposits in cardiac and axonal cells are the primary cause of this clinical syndrome. Treatment options are limited, but new drugs are being developed. Patisiran, a novel drug, is a liposomal siRNA against TTR that specifically targets this protein, reducing the accumulation of TTR in tissues, with subsequent improvement in both neuropathy and cardiac function. Patisiran is likely to serve as a prototype for the development of further intelligent drug solutions for use in targeted therapy. In this review we summarize the evidence currently available on the treatment of polyneuropathy in people with ATTRv with patisiran. We review the evidence on its efficacy, safety, and indications of use, citing novel and seminal papers on these subjects.

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“…44 Moreover, the Food and Drug Administration (FDA) has only approved two RNA interference (RNAi)-based therapies in the last 20 years. [45][46] Therefore…”

Recent Progress in Bioconjugation Strategies for Liposome-Mediated Drug Delivery

“…The liposomal portion of Onpattro ® is composed of ionizable cationic lipids (DLin-MC3-DMA), phospholipid (DSPC), cholesterol, and PEG2000-C-DMG, combined via rapid mixing under acidic pH. The drug is encapsulated as pH neutralizes, whereby smaller liposomes fuse into a large lipid nanoparticle [125]. In the body, the liposome is directed to the endosome, where DLin-MC3-DMA becomes cationic due to the low pH.…”

“…Following this localization to the endosome, osmotic swelling occurs within the endosome, resulting in until endosomal rupture and allowing the encapsulated siRNA to reach the cytosol. There, the siRNA inhibits synthesis of the transthyretin protein, decreasing its levels in serum and tissue deposits [125]. During Phase III clinical trials, Onpattro ® showed an 81% reduction in transthyretin production and improved muscle strength, sensation, reflexes, and heart rate compared to patients treated with a placebo [118,126].…”

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“…Similarly, siRNA binds to specific mRNA sequences with strict complementarity and inhibits its expression [ 17 ]. The clinical potential of targeting the RNAi pathways is highlighted by the recent FDA approval of ONPATTRO/Patisiran, which uses a lipid-based siRNA nanoparticle complex for the treatment of hereditary transthyretin (hATTR) amyloidosis [ 18 ].…”