Efficacy of T-cell transcription factor–specific DNAzymes in murine skin inflammation models

Purath, Ulrich; Ibrahim, Rouba; Zeitvogel, Jana; Renz, Harald; Runkel, Frank; Schmidts, Thomas; Dobler, Dorota; Werfel, Thomas; Müller, Anke; Garn, Holger

doi:10.1016/j.jaci.2015.09.022

Cited by 6 publications

(4 citation statements)

References 10 publications

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“…Emerging approaches using antisense molecules to target T H subset transcription factors improved inflammation in murine skin, possibly representing a new and promising strategy for treating inflammatory skin diseases. 141…”

Section: Endotype-based Targeted Therapeutic Approachesmentioning

confidence: 99%

Atopic dermatitis endotypes and implications for targeted therapeutics

Czarnowicki

Krueger

et al. 2019

Journal of Allergy and Clinical Immunology

459

480

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Recent research advancements indicate that atopic dermatitis (AD) is a complex disease characterized by different subtypes/ phenotypes based on age, disease chronicity, ethnicity, filaggrin and IgE status, and underlying molecular mechanisms/ endotypes. This heterogeneity advocates against the traditional ''one-size-fits-all'' therapeutic approaches still used to manage AD. Precision medicine approaches, striving for targeted, tailored, endotype-driven disease prevention and treatment, rely on detailed definitions of the disease's variability across different phenotypes. Studies have shown that AD harbors different endotypes across different age groups and ethnicities and according to IgE levels and filaggrin mutation status. These include European American versus Asian patients, children versus adults, intrinsic versus extrinsic (IgE status) disease, and patients with and without filaggrin mutations. Therapies targeting different cytokine axes and other mechanisms involved in disease pathogenesis, which are currently being tested for patients with AD across the disease spectrum, will INFORMATION FOR CATEGORY 1 CME CREDIT Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.

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Section: Endotype-based Targeted Therapeutic Approachesmentioning

confidence: 99%

Atopic dermatitis endotypes and implications for targeted therapeutics

Czarnowicki

Krueger

et al. 2019

Journal of Allergy and Clinical Immunology

459

480

View full text Add to dashboard Cite

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“…These modular endonucleases can be directed to cleave RNAs of interest, providing a route to synthetic regulators of gene expression 1 , biosensors 7 , molecular computers 8 , 9 and nanoscale machines 10 , and potentially as programmable, highly specific gene silencing agents. Notable examples of clinical evaluation include variants of the hammerhead ribozyme 11 , 12 and the 10-23 DNAzyme, in particular “hgd40” targeting an RNA encoding a master transcription factor of type-2 immune responses (GATA-3), reported to show some efficacy in reducing inflammation in psoriasis, asthma and COPD 13 – 15 , and “Dz13” targeting c-Jun mRNA, explored as a cytotoxic agent in a range of neoplasias 16 . However, despite the promise of simple and programmable gene silencing agents that - unlike CRISPR Cas-based reagents - could be produced by solid-phase chemical synthesis and delivered exogenously, they have so far failed to have significant clinical impact despite persistent efforts for over 20 years 17 – 20 , underscoring the need for new, improved strategies for RNA-cleaving catalysts.…”

Section: Introductionmentioning

confidence: 99%

A modular XNAzyme cleaves long, structured RNAs under physiological conditions and enables allele-specific gene silencing

et al. 2022

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Nucleic acid catalysts (ribozymes, DNA- and XNAzymes) cleave target (m)RNAs with high specificity but have shown limited efficacy in clinical application. Here we report on the in vitro evolution and engineering of a highly specific modular RNA endonuclease XNAzyme, FR6_1, composed of 2’-deoxy-2’-fluoro-β-D-arabino nucleic acid (FANA). FR6_1 overcomes activity limitations of previous DNA- and XNAzymes and can be retargeted to cleave highly structured full-length (>5 kb) BRAF and KRAS mRNAs at physiological Mg 2+ concentrations with allelic selectivity for tumour-associated ( BRAF V600E and KRAS G12D) mutations. Phosphorothioate-FANA modification enhances FR6_1 biostability and enables rapid KRAS mRNA knockdown in cultured human adenocarcinoma cells with a G12D-allele-specific component provided by in vivo XNAzyme cleavage activity. These results provide a starting point for the development of improved gene silencing agents based on FANA or other XNA chemistries.

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“…Provided that upcoming clinical studies in moderate to severe symptomatic asthmatics will be successful this new therapeutic strategy may be applied in patients that remain uncontrolled by standard GINA guideline therapies before monoclonal antibodies will be considered. Moreover, other allergic and/or type‐2‐driven indications such as atopic dermatitis and ulcerative colitis, for both of which the preclinical proof‐of principle was recently established , food allergies, eosinophilic COPD, eosinophilic esophagitis, and others may also profit from the novel treatment concept following appropriate formulation of the active compound for local delivery. Thus, the described approach of targeting the transcription factor GATA‐3 may be viewed as the beginning of a new era of asthma and allergy therapies and beyond these conditions.…”

Section: Resultsmentioning

confidence: 99%

GATA‐3‐specific DNAzyme — A novel approach for stratified asthma therapy

Garn

Renz

2017

Eur J Immunol

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It is now well established that type-2 immune mechanisms drive the inflammation in about 50% of asthma patients. The major cellular and molecular players regulating this important network have been identified. In terms of therapeutic intervention, cytokine and cytokine-receptor pathways have been given major attention, since these molecules are relatively easily accessible for a blockade through monoclonal antibodies, and a number of positive clinical results support this concept. However, targeting events controlling the type-2 immunity network upstream of selective cytokine pathways would be equally attractive. Type-2 immunity is regulated through a delicate interplay of several transcription factors (including GATA-3, STAT-6, NFAT, IRF4, c-maf), with GATA-3 as master regulator in this regard. Since transcription factors are intracellularly located they cannot be directly targeted by monoclonal antibodies. For intracellular targets, antisense technologies such as antisense DNA and siRNA have been shown to be a promising approach, and have recently made major advances toward clinical application. Here, we summarize the development of a GATA-3-specific DNAzyme-a molecule class that combines the superior specificity of antisense molecules with an inherent RNA-cleaving enzymatic activity-for the treatment of type-2-driven asthma from preclinical development toward a proof-of-concept clinical study.Keywords: allergy r asthma r DNAzyme r GATA-3 r Th2 r type-2 immune responses

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Efficacy of T-cell transcription factor–specific DNAzymes in murine skin inflammation models

Cited by 6 publications

References 10 publications

Atopic dermatitis endotypes and implications for targeted therapeutics

Atopic dermatitis endotypes and implications for targeted therapeutics

A modular XNAzyme cleaves long, structured RNAs under physiological conditions and enables allele-specific gene silencing

GATA‐3‐specific DNAzyme — A novel approach for stratified asthma therapy

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