Antisense- and RNA interference-based therapeutic strategies in allergy

Abstract

Modern therapeutic methods for manipulation of gene expression in allergic diseases have been receiving increased attention in the emerging era of functional genomics. With the growing application of gene silencing technologies, pharmacological modulation of translation represents a great advance in molecular therapy for allergy. Several strategies for sequence-specific post-transcriptional inhibition of gene expression can be distinguished: antisense oligonucleotides (AS-ONs), ribozymes (RZs), DNA enzymes (DNAzymes), and RNA interference (RNAi) triggered by small interfering RNAs (siRNAs). Potential anti-mRNA drugs in asthma and other allergic disorders may be targeted to cell surface receptors (adenosine A 1 receptor, high-affinity receptor Fc-ε RI-α, cytokine receptors), adhesion molecules and ligands (ICAM-1, VLA-4), ion channels (calcium-dependent chloride channel-1), cytokines and related factors (IL-4, IL-5, IL-13, SCF, TNF-α, TGF-β1), intracellular signal transduction molecules, such as tyrosine-protein kinases (Syk, Lyn, Btk), serine/threonine-protein kinases (p38 α MAP kinase, Raf-1), non-kinase signaling proteins (RasGRP4), and transcription factors involved in Th2 differentiation and allergic inflammation (STAT-6, GATA-3, NF-κB). The challenge to scientists is to determine which of the candidate targets warrants investment of time and resources. New-generation respirable AS-ONs, external guide sequence ribozymes, and RNA interference-based therapies have the potential to satisfy unmet needs in allergy treatment, acting at a more proximal level to a key etiopathogenetic molecular process, represented by abnormal expression of genes. Moreover, antisense and siRNA technologies imply a more rational design of new drugs for allergy.

A Short Hairpin DNA Analogous to miR-125b Inhibits C-Raf Expression, Proliferation, and Survival of Breast Cancer Cells

“…3 Most asDNAs and ODNs activate RNases H, which cleave and degrade the RNA of DNA-RNA hybrids (15,20,52,53). AsDNA can also block translation by steric hindrance of the ribosomes (14,54,55), and miRs primarily inhibit translation of proteins (13,56). ODN-Raf as well as miR-125b did not lead to a reduction of c-raf-1 mRNA but reduced C-Raf protein levels by 50% (Figs.…”

Matrix metalloproteinase 12 silencing: A therapeutic approach to treat pathological lung tissue remodeling?

“…mRNA [112]. The siRNA approach is based on preventing a protein production instead of suppressing its activity and, therefore, affords the opportunity to provide greater efficacy in disease control and intervention.…”

Small interfering RNA against interleukin-5 decreases airway eosinophilia and hyper-responsiveness

“…Manipulation of gene expression in mRNA level is more efficient than in protein level because multiple copies of a protein (approximately 5000 copies) are produced by each mRNA. 21 Therefore, hybridizationbased antisense oligonucleotides and RNA interference are investigated for their therapeutic effect on asthma and other allergic diseases.…”