Antisense Therapy against CCR3 and the Common Beta Chain Attenuates Allergen-induced Eosinophilic Responses

Abstract

TPI ASM8 attenuates the allergen-induced increase in target gene mRNA and airway responses in subjects with mild asthma. Clinical trial registered with www.clinicaltrials.gov (NCT 00264966).

A Multi-Targeted Antisense Oligonucleotide-Based Therapy Directed at Phosphodiesterases 4 and 7 for COPD

“…The phase 2a studies that have been performed until now have not shown any of this potential toxicity but longer term studies are needed to confirm these results. Furthermore, to date AON have been delivered via inhalation of a nebulisate to asthma patients (Gauvreau et al 2008;Gauvreau 2010), but not to COPD patients who have severely decreased FEV 1 . How well this patient cohort inhales the nebulisate would need to be determined.…”

“…An initial Phase 2 study design does not test in COPD patients but rather in allergic asthmatic patients following inhaled allergen challenge (2009). Another AON drug, ASM8 designed specifically for asthma and as such has targets different from PXS TPI1100, has demonstrated clinical efficacy in this allergen challenge model (Gauvreau et al 2008;Gauvreau 2010) clearly showing the potential for the AON approach. An advantage of this allergen challenge model is that the studies are generally brief in duration and the fall in FEV 1 is a well-recognized response as well as the incorporation of monitoring induced sputum allows for other inflammatory indicators to be measured.…”

“…Firstly, as PXS TPI1100 is administered via inhalation, it is delivered directly to the intended site of action of the lung (Ali et al 2001;Duan et al 2005;Gauvreau et al 2008;Guimond et al 2008) where the drug can enter target cells directly (Zhang et al 2004;Griesenbach et al 2006) thus potentially reducing total dose as compared to orally-available treatments. A further advantage of pulmonary administration of AON is that they are principally www.intechopen.com A Multi-Targeted Antisense Oligonucleoitde-Based Therapy Directed at Phosphodiesterases 4 and 7 for COPD 449 metabolized in the lung with very limited systemic delivery after inhalation (Templin et al 2000;Ali et al 2001;Guimond et al 2008) which leads to reduced systemic bioavailability of the drug.…”

Development of siRNA Technology to Prevent Scar Formation in Tendon Repair

“…This general concept can be harnessed experimentally and therapeutically by the delivery of anti-sense RNAs. Human trials are underway to regulate protein and gene expression to modify diseases such as leukemia, Duchenne Muscular Dystrophy, and inflammatory conditions [3][4][5] . Among the challenges with RNA therapies is the relatively unstable nature of RNAs.…”

Targeting eosinophils in asthma: current and future state of cytokine- and chemokine-directed monoclonal therapy

“…The antisense oligonucleotide TPI ASM8 targeted against CCR3 had some effect in reducing sputum eosinophils and airway inflammation in response to allergen provocation in patients with mild atopic asthma. However, TPI ASM8 also contains an antisense oligonucleotide against the common b-chain of the receptors for IL-3, IL-5 and granulocyte-macrophage colony-stimulating factor, making the results difficult to interpret in terms of a specific effect on CCR3 antagonism [23]. However, TPI ASM8 may prove to be more effective if tested using larger patient numbers with more severe allergic asthma who exhibit a sputum eosinophilia associated with disease exacerbation; an approach that might validate targeting more than one asthma-relevant cytokine/chemokine.…”