The current landscape of nucleic acid therapeutics

Nature Nanotechnology, Journal Year: 2021, Volume and Issue: 16(6), P. 630 - 643

Published: May 31, 2021

The increasing number of approved nucleic acid therapeutics demonstrates the potential to treat diseases by targeting their genetic blueprints in vivo. Conventional treatments generally induce therapeutic effects that are transient because they target proteins rather than underlying causes. In contrast, can achieve long-lasting or even curative via gene inhibition, addition, replacement editing. Their clinical translation, however, depends on delivery technologies improve stability, facilitate internalization and increase affinity. Here, we review four platform have enabled translation therapeutics: antisense oligonucleotides, ligand-modified small interfering RNA conjugates, lipid nanoparticles adeno-associated virus vectors. For each platform, discuss current state-of-the-art approaches, explain rationale behind its development, highlight technological aspects facilitated provide an example a clinically relevant drug. how these enable development cutting-edge drugs, such as tissue-specific bioconjugates, messenger gene-editing therapeutics. This Review provides overview currently used clinic for therapeutics, describing properties, discussing technical advancements led approval, highlighting examples drugs make use technologies.

Language: Английский

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Drug delivery systems for RNA therapeutics

Nature Reviews Genetics, Journal Year: 2022, Volume and Issue: 23(5), P. 265 - 280

Published: Jan. 4, 2022

Language: Английский

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The role of lipid components in lipid nanoparticles for vaccines and gene therapy

Advanced Drug Delivery Reviews, Journal Year: 2022, Volume and Issue: 188, P. 114416 - 114416

Published: July 3, 2022

Language: Английский

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On the mechanism of tissue-specific mRNA delivery by selective organ targeting nanoparticles

Proceedings of the National Academy of Sciences, Journal Year: 2021, Volume and Issue: 118(52)

Published: Dec. 21, 2021

Significance Liver accumulation represents a significant barrier in the development of therapeutically efficacious nanoparticle drug delivery systems. Using series lipid nanoparticles with distinct organ-targeting properties, we provide evidence for plausible mechanism action to non-liver tissues. Following intravenous injection, specific proteins blood are recruited nanoparticle’s surface based on its molecular composition and they endow it unique biological identity that governs ultimate fate body. An innovative paradigm emerges from this mechanistic understanding delivery—endogenous targeting—wherein is rationally engineered interact overcome liver target organs.

Language: Английский

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Solid Lipid Nanoparticles for Drug Delivery: Pharmacological and Biopharmaceutical Aspects

Frontiers in Molecular Biosciences, Journal Year: 2020, Volume and Issue: 7

Published: Oct. 30, 2020

In the golden age of pharmaceutical nanocarriers, we are witnessing a maturation stage original concepts and ideas. There is no doubt that nanoformulations extremely valuable tools for drug delivery applications; current challenge how to optimize them ensure they safe, effective scalable, so can be manufactured at an industrial level advance clinical use. this context, lipid nanoparticles have gained ground, since generally regarded as non-toxic, biocompatible easy-to-produce formulations. Pharmaceutical applications nanocarriers burgeoning field transport diversity therapeutic agents, from biotechnological products small molecules. This review starts with brief overview characteristics solid discusses relevancy performing systematic preformulation studies. The main applications, well advantages type nanovehicles offers in certain scenarios discussed. Next, pharmacokinetic aspects described, such routes administration, absorption after oral distribution organism (including brain penetration) elimination processes. Safety toxicity issues also addressed. Our work presents point view, addressing biopharmaceutical these by means descriptive statistics state-of-the-art research. All presented results, trends, graphs discussions based (and reproducible) bibliographic search considered only papers subject, covering 7 years range (2013-today), period accounts more than 60% total number publications topic databases engines. Focus was placed on fields application, processes efforts translation into practice lipid-based nanoparticles. For this, currently active trials were reviewed, discussion what achievements or milestones still reached, way understanding reasons scarce undergoing trials.

Language: Английский

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The mRNA-LNP platform's lipid nanoparticle component used in preclinical vaccine studies is highly inflammatory

iScience, Journal Year: 2021, Volume and Issue: 24(12), P. 103479 - 103479

Published: Nov. 20, 2021

Vaccines based on mRNA-containing lipid nanoparticles (LNPs) are a promising new platform used by two leading vaccines against COVID-19. Clinical trials and ongoing vaccinations present with varying degrees of protection levels side effects. However, the drivers reported effects remain poorly defined. Here we evidence that Acuitas' LNPs in preclinical nucleoside-modified mRNA vaccine studies highly inflammatory mice. Intradermal intramuscular injection these led to rapid robust responses, characterized massive neutrophil infiltration, activation diverse pathways, production various cytokines chemokines. The same dose LNP delivered intranasally similar responses lung resulted high mortality rate, mechanism unresolved. Thus, mRNA-LNP platforms' potency supporting induction adaptive immune observed may stem from LNPs' nature.

Language: Английский

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Lipids and Lipid Derivatives for RNA Delivery

Chemical Reviews, Journal Year: 2021, Volume and Issue: 121(20), P. 12181 - 12277

Published: July 19, 2021

RNA-based therapeutics have shown great promise in treating a broad spectrum of diseases through various mechanisms including knockdown pathological genes, expression therapeutic proteins, and programmed gene editing. Due to the inherent instability negative-charges RNA molecules, can make most use delivery systems overcome biological barriers release payload into cytosol. Among different types systems, lipid-based particularly lipid nanoparticles (LNPs), been extensively studied due their unique properties, such as simple chemical synthesis components, scalable manufacturing processes LNPs, wide packaging capability. LNPs represent widely used for therapeutics, evidenced by clinical approvals three LNP-RNA formulations, patisiran, BNT162b2, mRNA-1273. This review covers recent advances lipids, derivatives, lipid-derived macromolecules over past several decades. We focus mainly on structures, synthetic routes, characterization, formulation methods, structure–activity relationships. also briefly describe current status representative preclinical studies trials highlight future opportunities challenges.

Language: Английский

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Lipid Nanoparticle Technology for Clinical Translation of siRNA Therapeutics

Accounts of Chemical Research, Journal Year: 2019, Volume and Issue: 52(9), P. 2435 - 2444

Published: Aug. 9, 2019

Delivering nucleic acid-based therapeutics to cells is an attractive approach target the genetic cause of various diseases. In contrast conventional small molecule drugs that gene products (i.e., proteins), induce therapeutic effects by modulating expression. Gene silencing, process whereby protein production prevented neutralizing its mRNA template, a potent strategy in highly precise manner. Importantly, silencing has broad potential as theoretically any disease-causing can be targeted. It was demonstrated two decades ago introducing synthetic interfering RNAs (siRNAs) into cytoplasm results specific degradation complementary via called RNA interference (RNAi). Since then, significant efforts and investments have been made exploit RNAi therapeutically advance siRNA clinic. Utilizing (unmodified) therapeutic, however, challenging due limited bioavailability following systemic administration. Nuclease activity renal filtration result siRNA's rapid clearance from circulation administration induces (innate) immune responses. Furthermore, unfavorable physicochemical characteristics largely prevent diffusion across cellular membranes, impeding ability reach where it engage machinery. The clinical translation therefore dependent on chemical modifications developing sophisticated delivery platforms improve their stability, limit activation, facilitate internalization, increase affinity. These developments resulted last year's approval first Onpattro (patisiran), for treatment hereditary amyloidogenic transthyretin (TTR) amyloidosis. This disease characterized mutation encoding TTR, serum transports retinol secretion liver. leads misfolded proteins deposit amyloid fibrils multiple organs, resulting progressive neurodegeneration. Patisiran's effect relies siRNA-mediated TTR preventing mutant halting or even reversing progression. For efficient hepatocytes, patisiran critically lipid nanoparticle (LNP) technology. this Account, we provide overview key advances crucial LNP technology, explain how these contributed parenteral We discuss optimization formulation, particularly focusing rational design ionizable cationic lipids poly(ethylene glycol) lipids. components proven instrumental encapsulation, favorable pharmacokinetic parameters, hepatocyte internalization. Additionally, pay attention development mixing-based methods robust scalable procedures. Finally, highlight patisiran's technology's enable beyond current state-of-the-art, such editing therapeutics.

Language: Английский

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Antisense Oligonucleotides: An Emerging Area in Drug Discovery and Development

Journal of Clinical Medicine, Journal Year: 2020, Volume and Issue: 9(6), P. 2004 - 2004

Published: June 26, 2020

Antisense oligonucleotides (ASOs) bind sequence specifically to the target RNA and modulate protein expression through several different mechanisms. The ASO field is an emerging area of drug development that targets disease source at level offers a promising alternative therapies targeting downstream processes. To translate ASO-based into clinical success, it crucial overcome challenges associated with off-target side effects insufficient biological activity. In this regard, chemical modifications diverse delivery strategies have been explored. review, we systematically discuss modifications, mechanism action, optimized classes ASOs. Further, highlight recent advances made in drugs focus on are approved by Food Drug Administration (FDA) European Medicines Agency (EMA) for applications. We also various candidates trials, outstanding opportunity microRNA as viable therapeutic future therapies.

Language: Английский

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Lipid-Based Nanoparticles in the Clinic and Clinical Trials: From Cancer Nanomedicine to COVID-19 Vaccines

Vaccines, Journal Year: 2021, Volume and Issue: 9(4), P. 359 - 359

Published: April 8, 2021

COVID-19 vaccines have been developed with unprecedented speed which would not possible without decades of fundamental research on delivery nanotechnology. Lipid-based nanoparticles played a pivotal role in the successes and many other nanomedicines, such as Doxil

Language: Английский

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