Antisense therapy against CCR3 and the common beta chain attenuates allergen-induced eosinophilic responses

Am J Respir Crit Care Med. 2008 May 1;177(9):952-8. doi: 10.1164/rccm.200708-1251OC. Epub 2008 Jan 31.


Rationale: The drug product TPI ASM8 contains two modified phosphorothioate antisense oligonucleotides designed to inhibit allergic inflammation by down-regulating human CCR3 and the common beta chain (beta(c)) of IL-3, IL-5, and granulocyte-macrophage colony-stimulating factor receptors.

Objectives: This study examined the effects of inhaled TPI ASM8 on sputum cellular influx, CCR3 and beta(c) mRNA and protein levels, and the airway physiologic response after inhaled allergen.

Methods: Seventeen subjects with mild atopic asthma were randomized in a crossover study to inhale 1,500 microg TPI ASM8 or placebo by nebulizer, once daily for 4 days. On Day 3, subjects underwent allergen inhalation challenge. Sputum samples were collected before and after allergen. CCR3 and beta(c) protein levels were measured by flow cytometry, mRNA was measured using real-time quantitative polymerase chain reaction, and the FEV1 was measured over 7 hours after challenge.

Measurements and main results: Compared with placebo, TPI ASM8 inhibited sputum eosinophil influx by 46% (P = 0.02) and blunted the increase in total cells (63%) after allergen challenge. TPI ASM8 significantly reduced the early asthmatic response (P = 0.04) with a trend for the late asthmatic response (P = 0.08). The allergen-induced (Day 2 to Day 3) levels of beta(c) mRNA and CCR3 mRNA in sputum-derived cells were inhibited by TPI ASM8 (P = 0.039 and P = 0.054, respectively), with no significant effects on the cell surface protein expression of CCR3 and beta(c) (P > 0.05). No serious adverse events were reported.

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

Trial registration: NCT00264966.

Publication types

  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Inhalation
  • Adult
  • Allergens / adverse effects*
  • Asthma / drug therapy*
  • Asthma / genetics
  • Asthma / metabolism
  • Cross-Over Studies
  • Double-Blind Method
  • Drug Combinations
  • Female
  • Flow Cytometry
  • Follow-Up Studies
  • Forced Expiratory Volume
  • Gene Expression
  • Humans
  • Male
  • Middle Aged
  • Nebulizers and Vaporizers
  • Oligonucleotides, Antisense / administration & dosage
  • Oligonucleotides, Antisense / therapeutic use*
  • Phosphorothioate Oligonucleotides / administration & dosage
  • Phosphorothioate Oligonucleotides / therapeutic use*
  • Pulmonary Eosinophilia / drug therapy*
  • Pulmonary Eosinophilia / genetics
  • Pulmonary Eosinophilia / metabolism
  • RNA, Messenger / genetics
  • Receptors, CCR3 / antagonists & inhibitors*
  • Receptors, CCR3 / genetics
  • Receptors, CCR3 / metabolism
  • Receptors, Cytokine / genetics
  • Receptors, Cytokine / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sputum / cytology
  • Sputum / metabolism
  • Treatment Outcome


  • Allergens
  • CCR3 protein, human
  • Drug Combinations
  • Oligonucleotides, Antisense
  • Phosphorothioate Oligonucleotides
  • RNA, Messenger
  • Receptors, CCR3
  • Receptors, Cytokine
  • TPI ASM8
  • beta C receptor

Associated data