si<scp>RNA</scp> Targeting and Treatment of Gastrointestinal Diseases

Chevalier, Rachel

doi:10.1111/cts.12668

Cited by 14 publications

(10 citation statements)

References 107 publications

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“…Simplified and generally speaking, ASO can bind to complementary pre-mRNA or mRNA and alter splicing or induce degradation by endogenous RNase H, respectively, whereas siRNA binds to endogenous RNA-induced silencing complex and thereby induces mRNA degradation. Both approaches aim to silence target genes (reviewed in: [ 74 , 81 , 82 , 83 , 84 , 85 ]). However, miRNA are endogenously produced small, non-coding RNA strands of typically 20–25 nucleotides long that are implied in several cellular and gene regulation processes (reviewed in: [ 86 , 87 ]).…”

Section: Preclinical Studies On Local Tnf-α Inhibitionmentioning

confidence: 99%

“…Targeted cytoplasmic nucleotide delivery is a prerequisite for gene silencing. To deliver nucleotides to targeted cells, the formulation must protect the nucleotides from environmental degradation, aid in targeted cellular uptake by endocytosis, and must facilitate endosomal escape of the nucleotides into the cytoplasm [ 73 , 82 , 83 ]. These processes can be influenced by different approaches and formulation strategies of which several are discussed in this review.…”

Section: Preclinical Studies On Local Tnf-α Inhibitionmentioning

confidence: 99%

See 1 more Smart Citation

Review: Local Tumor Necrosis Factor-α Inhibition in Inflammatory Bowel Disease

et al. 2020

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Crohn’s disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) characterized by intestinal inflammation. Increased intestinal levels of the proinflammatory cytokine tumor necrosis factor-α (TNF-α) are associated with disease activity and severity. Anti-TNF-α therapy is administered systemically and efficacious in the treatment of IBD. However, systemic exposure is associated with adverse events that may impede therapeutic treatment. Clinical studies show that the efficacy correlates with immunological effects localized in the gastrointestinal tract (GIT) as opposed to systemic effects. These data suggest that site-specific TNF-α inhibition in IBD may be efficacious with fewer expected side effects related to systemic exposure. We therefore reviewed the available literature that investigated the efficacy or feasibility of local TNF-α inhibition in IBD. A literature search was performed on PubMed with given search terms and strategy. Of 8739 hits, 48 citations were included in this review. These studies ranged from animal studies to randomized placebo-controlled clinical trials. In these studies, local anti-TNF-α therapy was achieved with antibodies, antisense oligonucleotides (ASO), small interfering RNA (siRNA), microRNA (miRNA) and genetically modified organisms. This narrative review summarizes and discusses these approaches in view of the clinical relevance of local TNF-α inhibition in IBD.

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Section: Preclinical Studies On Local Tnf-α Inhibitionmentioning

confidence: 99%

Section: Preclinical Studies On Local Tnf-α Inhibitionmentioning

confidence: 99%

Review: Local Tumor Necrosis Factor-α Inhibition in Inflammatory Bowel Disease

et al. 2020

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“…Hepatocytes have been favored for proof-of-concept work given their high blood flow and abundance of the liver-specific asialoglycoprotein receptor (ASGPR). , ASGPR ligand N -acetylgalactosamine (GalNAc) is often covalently conjugated to siRNA for hepatic delivery. ,− A schematic of sc delivery of ligand-conjugated siRNA is provided in Figure . Extrahepatic delivery of siRNA remains an ongoing challenge. − siRNA is taken up into the cell via the endosomal pathway and must escape before being shunted into the lysosome for degradation . Although published quantitative data are limited, it is generally believed that only a small fraction of internalized drug is released into the cytosol. − …”

Section: Part 1: Therapeutic Strategy and Sar In Drug Developmentmentioning

confidence: 99%

Emerging siRNA Design Principles and Consequences for Biotransformation and Disposition in Drug Development

et al. 2020

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After two decades teetering at the intersection of laboratory tool and therapeutic reality, with two siRNA drugs now clinically approved, this modality has finally come into fruition. Consistent with other emerging modalities, initial proof-of-concept efforts concentrated on coupling pharmacologic efficacy with desirable safety profiles. Consequently, thorough investigations of siRNA absorption, distribution, metabolism, and excretion (ADME) properties are lacking. Advancing ADME knowledge will aid establishment of in vitro–in vivo correlations and pharmacokinetic–pharmacodynamic relationships to optimize candidate selection through discovery and translation. Here, we outline the emerging siRNA design principles and discuss the consequences for siRNA disposition and biotransformation. We propose a conceptual framework for siRNA ADME evaluation, contextualizing the site of biotransformation product formation with PK–PD modulation, and end with a discussion around safety and regulatory considerations and future directions for this modality.

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“…In the case of siRNA, the antisense strand binds to fully complementary mRNA, resulting in mRNA cleavage. In the case of mRNA, the antisense strand binds to target mRNAs that are partially complementary to it, resulting in target gene silencing via translational repression, cleavage, and/or degradation (Figure 1) [8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Liposomes for Targeting RNA Interference-Based Therapy in Inflammatory Bowel Diseases

Alfagih¹

2023

Liposomes - Recent Advances, New Perspectives and Applications

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The discovery of RNA interference (RNAi) in mammalian cells in 2001 opened up a new class of candidate therapeutics for hard-to-cure diseases like inflammatory bowel diseases. The main challenge for the development of RNAi-based therapeutics is the efficient and safe delivery of RNAi since the RNAi machinery is housed in the cytoplasm. Among the various approaches to active targeting, liposome-based delivery systems are innovative and promising systems to transport and control RNAi molecules release and overcome some of their limitations. Many RNAis in lipid formulations have progressed through various stages of clinical trials, with the measurable improvements in patients and no side effects. For colon targeting, liposomes can be manipulated by different methods. This chapter discusses the progress in delivering RNAi molecules to the colon using liposomes.

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siRNA Targeting and Treatment of Gastrointestinal Diseases

Cited by 14 publications

References 107 publications

Review: Local Tumor Necrosis Factor-α Inhibition in Inflammatory Bowel Disease

Review: Local Tumor Necrosis Factor-α Inhibition in Inflammatory Bowel Disease

Emerging siRNA Design Principles and Consequences for Biotransformation and Disposition in Drug Development

Liposomes for Targeting RNA Interference-Based Therapy in Inflammatory Bowel Diseases

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