Development of siRNA Therapeutics for the Treatment of Liver Diseases

Holm, Anja; Løvendorf, Marianne B.; Kauppinen, Sakari

doi:10.1007/978-1-0716-1298-9_5

Cited by 7 publications

(7 citation statements)

References 37 publications

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“…They have gained extensive usage, including two approved mRNA vaccines on the market against SARS-CoV-2. Nevertheless, conventional LNPs are difficult to specifically target extrahepatic organs [ 55 ]. So far, the focus has shifted to designing delivery systems that can effectively deliver therapeutic agents to targeted tissues and cells [ 253 ].…”

Section: Outlook and Conclusionmentioning

confidence: 99%

Delivery of nucleic acids using nanomaterials

Qin,

Ou,

Zha

et al. 2023

Mol Biomed

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The increasing number of approved nucleic acid therapeutics demonstrates the potential for the prevention and treatment of a broad spectrum of diseases. This trend underscores the significant impact and promise of nucleic acid-based treatments in the field of medicine. Nevertheless, employing nucleic acids as therapeutics is challenging due to their susceptibility to degradation by nucleases and their unfavorable physicochemical characteristics that hinder delivery into cells. Appropriate vectors play a pivotal role in improving nucleic acid stability and delivering nucleic acids into specific cells. The maturation of delivery systems has led to breakthroughs in the development of therapeutics based on nucleic acids such as DNA, siRNA, and mRNA. Non-viral vectors have gained prominence among the myriad of nanomaterials due to low immunogenicity, ease of manufacturing, and simplicity of cost-effective, large-scale production. Here, we provide an overview of the recent advancements in nanomaterials for nucleic acid delivery. Specifically, we give a detailed introduction to the characteristics of polymers, lipids, and polymer-lipid hybrids, and provide comprehensive descriptions of their applications in nucleic acid delivery. Also, biological barriers, administration routes, and strategies for organ-selective delivery of nucleic acids are discussed. In summary, this review offers insights into the rational design of next-generation delivery vectors for nucleic acid delivery.

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Section: Outlook and Conclusionmentioning

confidence: 99%

Delivery of nucleic acids using nanomaterials

Qin,

Ou,

Zha

et al. 2023

Mol Biomed

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“…Vutrisiran is a GalNAc-conjugated siRNA-drug administered s.c. once every three months and was developed by Alnylam Pharmaceuticals[ 87 ]. Conjugating the siRNA with a GalNac moiety allows for selective delivery of the RNA drug to hepatocytes in the liver[ 88 ].…”

Section: Clinical Development Of Rna Medicines For Treatment Of Neuro...mentioning

confidence: 99%

“…Up to 83% reduction of TTR after a single 25 mg dose of vutrisiran was observed, and there were no drug-related discontinuations or deaths after nine months[ 87 ]. Currently, there are two RNA drugs approved and commercialized for the treatment of TTR, patisiran and inotersen developed by Alnylam and Ionis, respectively[ 88 ].…”

Section: Clinical Development Of Rna Medicines For Treatment Of Neuro...mentioning

confidence: 99%

Clinical advances of RNA therapeutics for treatment of neurological and neuromuscular diseases

Holm

Hansen²,

Klitgaard³

et al. 2022

RNA Biology

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RNA therapeutics comprise a diverse group of oligonucleotide-based drugs such as antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), and short hairpin RNAs (shRNAs) that can be designed to selectively interact with drug targets currently undruggable with small molecule-based drugs or monoclonal antibodies. Furthermore, RNA-based therapeutics have the potential to modulate entire disease pathways, and thereby represent a new modality with unprecedented potential for generating disease-modifying drugs for a wide variety of human diseases, including central nervous system (CNS) disorders. Here, we describe different strategies for delivering RNA drugs to the CNS and review recent advances in clinical development of ASO drugs and siRNA-based therapeutics for the treatment of neurological diseases and neuromuscular disorders. Abbreviations 2’-MOE: 2’- O -(2-methoxyethyl); 2’- O -Me: 2’- O -methyl; 2’-F: 2’-fluoro; AD: Alzheimer's disease; ALS: Amyotrophic lateral sclerosis; ALSFRS-R: Revised Amyotrophic Lateral Sclerosis Functional Rating Scale; ARC: Antibody siRNA Conjugate; AS: Angelman Syndrome; ASGRP: Asialoglycoprotein receptor; ASO: Antisense oligonucleotide; AxD: Alexander Disease; BBB: Blood brain barrier; Bp: Basepair; CNM: Centronuclear myopathies; CNS: Central Nervous System; CPP: Cell-penetrating Peptide; CSF: Cerebrospinal fluid; DMD: Duchenne muscular dystrophy; DNA: Deoxyribonucleic acid; FAP: Familial amyloid polyneuropathy; FALS: Familial amyotrophic lateral sclerosis; FDA: The United States Food and Drug Administration; GalNAc: N-acetylgalactosamine; GoF: Gain of function; hATTR: Hereditary transthyretin amyloidosis; HD: Huntington's disease; HRQOL: health-related quality of life; ICV: Intracerebroventricular; IT: Intrathecal; LNA: Locked nucleic acid; LoF: Loss of function; mRNA: Messenger RNA; MS: Multiple Sclerosis; MSA: Multiple System Atrophy; NBE: New Biological Entity; NCE: New Chemical Entity; NHP: Nonhuman primate; nt: Nucleotide; PD: Parkinson's disease; PNP: Polyneuropathy; PNS: Peripheral nervous system; PS: Phosphorothioate; RISC: RNA-Induced Silencing Complex; RNA: Ribonucleic acid; RNAi: RNA interference; s.c.: Subcutaneous; siRNA: Small interfering RNA; SMA: Spinal muscular atrophy; SMN: Survival motor neuron; TTR: Transthyretin

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“…conjugates have entered clinical trials for the treatment of liver associated conditions (Holm et al, 2021). GalNActargeting relies on the specific high surface expression of ASPGR on hepatocytes ($500,000 receptors/cell) which allows for rapid receptor mediated endocytosis of GalNAc conjugates.…”

Section: Small Molecule Ligandsmentioning

confidence: 99%

“…Notably, asialoglycoprotein receptors (ASPGRs) expressed on hepatocytes can be targeted with trilvalent N‐acetylgalactoseamine‐ (GalNAc) conjugated siRNA and siRNA‐loaded LNPs (Akinc et al, 2010 ). GalNAc‐directed LNPs and siRNA both showed improved activity of siRNA in hepatocytes, and subsequently several GalNAc‐siRNA conjugates have entered clinical trials for the treatment of liver associated conditions (Holm et al, 2021 ). GalNAc‐targeting relies on the specific high surface expression of ASPGR on hepatocytes (~500,000 receptors/cell) which allows for rapid receptor mediated endocytosis of GalNAc conjugates.…”

Section: Controlling Delivery To Target Cellsmentioning

confidence: 99%

Nanoparticles for vaccine and gene therapy: Overcoming the barriers to nucleic acid delivery

Mollé

Smyth

Yuen

et al. 2022

WIREs Nanomed Nanobiotechnol

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Nucleic acid therapeutics can be used to control virtually every aspect of cell behavior and therefore have significant potential to treat genetic disorders, infectious diseases, and cancer. However, while clinically approved to treat a small number of diseases, the full potential of nucleic acid therapeutics is hampered by inefficient delivery. Nucleic acids are large, highly charged biomolecules that are sensitive to degradation and so the approaches to deliver these molecules differ significantly from traditional small molecule drugs. Current studies suggest less than 1% of the injected nucleic acid dose is delivered to the target cell in an active form. This inefficient delivery increases costs and limits their use to applications where a small amount of nucleic acid is sufficient. In this review, we focus on two of the major barriers to efficient nucleic acid delivery: (1) delivery to the target cell and (2) transport to the subcellular compartment where the nucleic acids are therapeutically active. We explore how nanoparticles can be modified with targeting ligands to increase accumulation in specific cells, and how the composition of the nanoparticle can be engineered to manipulate or disrupt cellular membranes and facilitate delivery to the optimal subcellular compartments. Finally, we highlight how with intelligent material design, nanoparticle delivery systems have been developed to deliver nucleic acids that silence aberrant genes, correct genetic mutations, and act as both therapeutic and prophylactic vaccines. This article is categorized under: Nanotechnology Approaches to Biology > Cells at the Nanoscale Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease Biology‐Inspired Nanomaterials > Lipid‐Based Structures

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Development of siRNA Therapeutics for the Treatment of Liver Diseases

Cited by 7 publications

References 37 publications

Delivery of nucleic acids using nanomaterials

Delivery of nucleic acids using nanomaterials

Clinical advances of RNA therapeutics for treatment of neurological and neuromuscular diseases

Nanoparticles for vaccine and gene therapy: Overcoming the barriers to nucleic acid delivery

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