Ongoing Clinical Trials of Nonviral siRNA Therapeutics

Abstract

Short interfering RNAs (siRNA) are a powerful class of genetic medicines whose clinical translation can be hindered by their suboptimal delivery properties in vivo.Here, we provide a clinically focused overview that summarizes ongoing siRNA clinical trials from the perspective of innovations in nonviral delivery strategies. More specifically, our review begins by highlighting the delivery barriers and physiochemical properties of siRNA that make it challenging to deliver it in vivo. We then provide commentary on specific delivery strategies, including sequence modification, siRNA ligand conjugation, and nanoparticle and exosomal packaging, each of which can be used to control the delivery of siRNA therapies in living systems. Last, we provide a summary table of ongoing siRNA clinical trials which also highlights the indication of use, target, and National Clinical Trial (NCT) number associated with each entry. In writing this review, our work aims to highlight the key challenges and strategies for effective nonviral siRNA delivery in vivo, while simultaneously summarizing information on ongoing clinical trials for siRNA therapy in humans.

Therapeutic synthetic and natural materials for immunoengineering

“…217 As previously mentioned, Patisiran, the first ever LNP-delivered siRNA-based drug, leverages the RNAi pathway to combat hereditary transthyretin-mediated amyloidosis by knocking down the production of pathogenic transthyretin protein and, since being FDA-approved in 2018, has kickstarted a flurry of FDA approvals of siRNA-based therapies. 218–220…”

Inorganic nanocarriers for siRNA delivery for cancer treatments

“…However, the naked delivery of siRNA has faced many challenges because of their inherent properties-i.e. high molecular weight and negative charge (make them difficult to enter into cells), instability in plasma, immunogenicity, intrinsic toxicity and so on [104][105][106]. Besides, the major barriers for siRNA-based RNAi are depending upon two major factors: (i) the area-of-therapeutic interest-that can be specific tissues or organs-whose accessibility can pose an issue for reaching of siRNA; and (ii) the administration routes (local and systemic)-herein, the local administration route can pose comparative lesser threat.…”

“…Another clinical study (NCT00363714) has also been started in the same year for treating the age-related macular degeneration via VEGF targeted siRNA. The number of clinical trial studies (as per 'clinicaltrials.gov') has increased from 18 (during 2004-2009) to 76 (during 2010-2019) for treating different diseases that include amyloidosis, acute hepatic porphyria, primary hyperoxaluria, atherosclerotic cardiovascular disease, hypercholesterolemia, acute coronary syndrome, haemophilia and so on [105,160,161]. In most of them, the delivery of siRNAs is aided by Nacetyl-d-galactosamine based nanocarrier.…”

Bioinspired Spatiotemporal Management toward RNA Therapies

“…89 A detailed GalNAc delivery system for clinical trials has been summarized in this review. 90 In addition, antibodies, proteins, or peptides are another attractive source of ligands, which enables RNA delivery to specific targeted tissue/cells and enhances the cell-penetrating or endosomolytic properties. For instance, cell penetrating peptides (CPPs), derived from biomolecules in humans such as HIV-1, could easily conjugate with RNA due to their amphipathic properties.…”

“…GalNAc, a carbohydrate moiety, has become one of the most attractive strategies for conjugating RNA due to its low cost and high liver silencing potential utilizing in different clinical trial phases. , It can bind to ASGR1 or ASPGR receptor (liver-expressed asialoglyco protein receptor 1), promoting the ASOs and siRNA uptakes by endocytosis. , Moreover, a GalNAc-conjugated siRNA called givosiran received FDA approval in 2019, which has been applied for the treatment of acute hepatic porphyria . A detailed GalNAc delivery system for clinical trials has been summarized in this review …”