Clinical pharmacology of siRNA therapeutics: current status and future prospects

ABSTRACT

Introduction

Small interfering RNA (siRNA) has emerged as a powerful tool for post-transcriptional downregulation of multiple genes for various therapies. Naked siRNA molecules are surrounded by several barriers that tackle their optimum delivery to target tissues such as limited cellular uptake, short circulation time, degradation by endonucleases, glomerular filtration, and capturing by the reticuloendothelial system (RES).

Areas covered

This review provides insights into studies that investigate various siRNA-based therapies, focusing on the mechanism, delivery strategies, bioavailability, pharmacokinetic, and pharmacodynamics of naked and modified siRNA molecules. The clinical pharmacology of currently approved siRNA products is also discussed.

Expert opinion

Few siRNA-based products have been approved recently by the Food and Drug Administration (FDA) and other regulatory agencies after approximately 20 years following its discovery due to the associated limitations. The absorption, distribution, metabolism, and excretion of siRNA therapeutics are highly restricted by several obstacles, resulting in rapid clearance of siRNA-based therapeutic products from systemic circulation before reaching the cytosol of targeted cells. The siRNA therapeutics however are very promising in many diseases, including gene therapy and SARS-COV-2 viral infection. The design of suitable delivery vehicles and developing strategies toward better pharmacokinetic parameters may solve the challenges of siRNA therapies.

KEYWORDS:

• Small interfering RNA (siRNA)
• bioavailability
• bioconjugation
• pharmacodynamic
• lumasiran
• givosiran
• patisiran

Article highlights

• siRNA is a promising tool that targets the mRNA of the gene of interest and degrades it, providing effective management of gene-associated diseases at an early step.

• The delivery of siRNA has many challenges which restrict its therapeutic application.

• The chemical modification of original siRNA molecules may optimize the bioavailability, pharmacokinetic, and therapeutic efficacy of siRNA.

• Bioconjugation of ligands such as aptamers, peptides, lipids, and carbohydrates shows a targeted transport of siRNA to desired cells with a developed clinical pharmacology profile.

• The siRNA therapeutics approved by the United States FDA represent a new approach to controlling challenging genetic and other diseases.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was supported by the Canadian Institute of Health Research [grant number: 201903PJT420512-PS-CFAA-47491]. Ahmed Abosalha is funded by a full scholarship from the Ministry of Higher Education of the Arab Republic of Egypt.