The Cytokines of Asthma

The basic immunology of asthma

BackgroundThe most prevalent phenotype of asthma is characterized by eosinophil-dominated inflammation that is driven by a type 2 helper T cell (Th2). Therapeutic targeting of GATA3, an important transcription factor of the Th2 pathway, may be beneficial. We evaluated the safety and efficacy of SB010, a novel DNA enzyme (DNAzyme) that is able to cleave and inactivate GATA3 messenger RNA (mRNA). MethodsWe conducted a randomized, double-blind, placebo-controlled, multicenter clinical trial of SB010 involving patients who had allergic asthma with sputum eosinophilia and who also had biphasic early and late asthmatic responses after laboratory-based allergen provocation. A total of 40 patients could be evaluated; 21 were assigned to receive 10 mg of SB010, and 19 were assigned to receive placebo, with each study drug administered by means of inhalation once daily for 28 days. An allergen challenge was performed before and after the 28-day period. The primary end point was the late asthmatic response as quanti...

/pdf/allergen-induced-asthmatic-responses-modified-by-a-gata3-4obx3o305i.pdf

Allergen-induced asthmatic responses modified by a GATA3-specific DNAzyme.

Allergic diseases are on the rise in the Western world and well-known allergy-protecting and -driving factors such as microbial and dietary exposure, pollution and smoking mediate their influence through alterations of the epigenetic landscape. Here, we review key facts on the involvement of epigenetic modifications in allergic diseases and summarize and critically evaluate the lessons learned from epigenome-wide association studies. We show the potential of epigenetic changes for various clinical applications: as diagnostic tools, to assess tolerance following immunotherapy or possibly predict the success of therapy at an early time point. Furthermore, new technological advances such as epigenome editing and DNAzymes will allow targeted alterations of the epigenome in the future and provide novel therapeutic tools.

Epigenetics and allergy: from basic mechanisms to clinical applications

The term asthma encompasses a disease spectrum with mild to very severe disease phenotypes whose traditional common characteristic is reversible airflow limitation. Unlike milder disease, severe asthma is poorly controlled by the current standard of care. Ongoing studies using advanced molecular and immunological tools along with improved clinical classification show that severe asthma does not identify a specific patient phenotype, but rather includes patients with constant medical needs, whose pathobiologic and clinical characteristics vary widely. Accordingly, in recent clinical trials, therapies guided by specific patient characteristics have had better outcomes than previous therapies directed to any subject with a diagnosis of severe asthma. However, there are still significant gaps in our understanding of the full scope of this disease that hinder the development of effective treatments for all severe asthmatics. In this Review, we discuss our current state of knowledge regarding severe asthma, highlighting different molecular and immunological pathways that can be targeted for future therapeutic development.

/pdf/current-concepts-of-severe-asthma-xo0g9ga63j.pdf

Current concepts of severe asthma.

Background Group 2 innate lymphoid cells (ILC2s) are effective producers of IL-5 and IL-13 during allergic inflammation and bridge the innate and adaptive immune responses. ILC2 numbers are increased in asthmatic patients compared with healthy control subjects. Thus far, human data describing their phenotype during acute allergic inflammation in the lung are incomplete. Objectives This study aims to characterize and compare blood- and lung-derived ILC2s before and after segmental allergen challenge in patients with mild-to-moderate asthma with high blood eosinophil counts (≥300 cells/μL). Methods ILC2s were isolated from blood and bronchoalveolar lavage (BAL) fluid before and after segmental allergen challenge. Cells were sorted by means of flow cytometry, cultured and analyzed for cytokine release or migration, and sequenced for RNA expression. Results ILC2s were nearly absent in the alveolar space under baseline conditions, but numbers increased significantly after allergen challenge (P  Conclusion ILC2s accumulate at the site of allergic inflammation and are recruited from the blood. Their transcriptional and functional activation pattern promotes type 2 inflammation.

Activation of group 2 innate lymphoid cells after allergen challenge in asthmatic patients.

To the Editor: Asthma comprises several clinical phenotypes associated with different pathophysiologically defined endotypes. There is medical need for novel endotype-specific treatment options that ideally interfere with upstream targets in the respective pathophysiologic pathways. The TH2-driven endotype represents a prominent subtype, and the transcription factor GATA-3 plays a key role in TH2 cell differentiation and activation by indispensably controlling TH2-derived cytokine (IL-4, IL-5, and IL-13) production. Sel et al reported DNAzymes, a new class of antisense molecules with inherent enzymatic activity that specifically bind to and subsequently cleave target RNA, that cleave GATA3 mRNA (see Fig E1 in this article’s Online Repository at www.jacionline.org). No major safety concerns were identified in a rigorous toxicology program for this drug

Safety and tolerability of a novel inhaled GATA3 mRNA targeting DNAzyme in patients with TH2-driven asthma.

SB010 (a nebulization solution of the human GATA-3-specific DNAzyme hgd40) has been developed for treatment of Th2-driven asthma. DNAzymes are single-stranded catalytic DNA molecules that specifically bind and cleave target mRNAs. Single or multiple applications of SB010 were already proven to be safe in Phase Ia studies in healthy subjects. Aim of this study was to investigate safety, tolerability and pharmacokinetics of inhaled single ascending doses of SB010 in a Phase Ib clinical trial in male stable allergic asthma patients with airway hyperresponsiveness (PC 20 methacholine ≤ 4 mg/mL). The study was performed as a randomized, double-blind, placebo controlled, parallel group (per dose level) dose-escalation study in 24 patients (18-45 years). SB010 was applied as nebulized solution via a controlled breathing system (AKITA 2 APIXNEB®) in 3 dose levels (5, 10, 20 mg). Adverse events (AEs), vital signs, clinical chemistry, hematology, urinalysis, ECG, pulmonary function testing, body temperature, and overall tolerability were assessed. Generally, all dose levels were well tolerated. No clinically relevant influence on safety laboratory parameters, vital signs including lung function tests, differential blood count, or ECG measurements was observed. Plasma concentrations were analyzed using a hgd40-specific hybridization ELISA system. Maximum plasma concentrations of hgd40 were detected within the highest dose group at 1 hour after administration (13.51 ± 17.02 pg/mL); hgd40 was no longer detectable at 6 hours after administration. SB010 is now under evaluation in a phase IIa study.

https://erj.ersjournals.com/content/erj/42/Suppl_57/4856.full.pdf

Safety profile and pharmacokinetics of an inhaled GATA-3-specific DNAzyme in a phase Ib study in patients with stable allergic asthma

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

Katrin Lüer

Author Tools

Chat about Author

Papers

Activation of group 2 innate lymphoid cells after allergen challenge in asthmatic patients.

Safety and tolerability of a novel inhaled GATA3 mRNA targeting DNAzyme in patients with TH2-driven asthma.

Safety profile and pharmacokinetics of an inhaled GATA-3-specific DNAzyme in a phase Ib study in patients with stable allergic asthma