Delivery of mRNA Therapeutics for the Treatment of Hepatic Diseases

Trepotec, Željka; Lichtenegger, Eva; Paar, Christian; Aneja, Manish Kumar; Rudolph, Carsten

doi:10.1016/j.ymthe.2018.12.012

Cited by 90 publications

(89 citation statements)

References 109 publications

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“…Delivery of mRNA can be mediated by viral and non-viral vectors. Non-viral vectors can further be categorized into lipid-based delivery systems, polymer-based delivery systems, and lipid-polymer hybrid systems [111]. For viral RNA delivery, there has been a great deal of interest in the engineering of adeno-associated viruses to carry nucleic acid cargoes [112].…”

Section: Viral Vectorsmentioning

confidence: 99%

Opportunities and Challenges in the Delivery of mRNA-Based Vaccines

et al. 2020

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In the past few years, there has been increasing focus on the use of messenger RNA (mRNA) as a new therapeutic modality. Current clinical efforts encompassing mRNA-based drugs are directed toward infectious disease vaccines, cancer immunotherapies, therapeutic protein replacement therapies, and treatment of genetic diseases. However, challenges that impede the successful translation of these molecules into drugs are that (i) mRNA is a very large molecule, (ii) it is intrinsically unstable and prone to degradation by nucleases, and (iii) it activates the immune system. Although some of these challenges have been partially solved by means of chemical modification of the mRNA, intracellular delivery of mRNA still represents a major hurdle. The clinical translation of mRNA-based therapeutics requires delivery technologies that can ensure stabilization of mRNA under physiological conditions. Here, we (i) review opportunities and challenges in the delivery of mRNA-based therapeutics with a focus on non-viral delivery systems, (ii) present the clinical status of mRNA vaccines, and (iii) highlight perspectives on the future of this promising new type of medicine.

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Section: Viral Vectorsmentioning

confidence: 99%

Opportunities and Challenges in the Delivery of mRNA-Based Vaccines

et al. 2020

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“…For example, unlike DNA, mRNA induces transient protein expression in the cytosol, avoiding the need for nuclear entry without risk of genome integration ( 18 ). Unlike direct delivery of proteins, the use of endogenous machinery to produce the therapeutic protein following mRNA delivery allows for natural posttranslational modifications to occur ( 14 ). However, similar to known delivery barriers in adults, the implementation of mRNA therapeutics for in utero therapy is met with several limitations including mRNA instability leading to rapid degradation and poor cellular uptake due to the negative charge of naked mRNA ( 19 , 20 ).…”

Section: Introductionmentioning

confidence: 99%

Ionizable lipid nanoparticles for in utero mRNA delivery

et al. 2021

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Clinical advances enable the prenatal diagnosis of genetic diseases that are candidates for gene and enzyme therapies such as messenger RNA (mRNA)–mediated protein replacement. Prenatal mRNA therapies can treat disease before the onset of irreversible pathology with high therapeutic efficacy and safety due to the small fetal size, immature immune system, and abundance of progenitor cells. However, the development of nonviral platforms for prenatal delivery is nascent. We developed a library of ionizable lipid nanoparticles (LNPs) for in utero mRNA delivery to mouse fetuses. We screened LNPs for luciferase mRNA delivery and identified formulations that accumulate within fetal livers, lungs, and intestines with higher efficiency and safety compared to benchmark delivery systems, DLin-MC3-DMA and jetPEI. We demonstrate that LNPs can deliver mRNAs to induce hepatic production of therapeutic secreted proteins. These LNPs may provide a platform for in utero mRNA delivery for protein replacement and gene editing.

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“…Clearly, hepatic disease has become a major global burden on human health. However, it is still a therapeutic challenge to develop hepatoprotective drugs with high efficacy and low side effects [1,3].…”

Section: Introductionmentioning

confidence: 99%

Zerumbone Protects against Carbon Tetrachloride (CCl4)-Induced Acute Liver Injury in Mice via Inhibiting Oxidative Stress and the Inflammatory Response: Involving the TLR4/NF-κB/COX-2 Pathway

Wang

Niu

et al. 2019

Molecules

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The natural compound Zerumbone (hereinafter referred to as ZER), a monocyclic sesquiterpenoid, has been reported to possess many pharmacological properties, including antioxidant and anti-inflammatory properties. This study aimed to investigate the underlying mechanism of ZER against acute liver injury (ALI) in CCl4-induced mice models. ICR mice were pretreated intraperitoneally with ZER for five days, then received a CCl4 injection two hours after the last ZER administration and were sacrificed 24 h later. Examination of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities and the histopathological analysis confirmed the hepatoprotective effect of ZER. Biochemical assays revealed that ZER pretreatment recovered the activities of antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), restored the glutathione (GSH) reservoir, and reduced the production of malondialdehyde (MDA), all in a dose-dependent manner. Furthermore, administration of ZER in vivo reduced the release amounts of pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) and inhibited the increased protein levels of Toll-like receptor 4 (TLR4), nuclear factor-kappaB (NF-κB) p-p65, and cyclooxygenase (COX-2). Further studies in lipopolysaccharide (LPS)-induced Raw264.7 inflammatory cellular models verified that ZER could inhibit inflammation via inactivating the TLR4/NF-κB/COX-2 pathway. Thus, our study indicated that ZER exhibited a hepatoprotective effect against ALI through its antioxidant and anti-inflammatory activities and the possible mechanism might be mediated by the TLR4/NF-κB/COX-2 pathway. Collectively, our studies indicate ZER could be a potential candidate for chemical liver injury treatment.

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Delivery of mRNA Therapeutics for the Treatment of Hepatic Diseases

Cited by 90 publications

References 109 publications

Opportunities and Challenges in the Delivery of mRNA-Based Vaccines

Opportunities and Challenges in the Delivery of mRNA-Based Vaccines

Ionizable lipid nanoparticles for in utero mRNA delivery

Zerumbone Protects against Carbon Tetrachloride (CCl4)-Induced Acute Liver Injury in Mice via Inhibiting Oxidative Stress and the Inflammatory Response: Involving the TLR4/NF-κB/COX-2 Pathway

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