title: TPI ASM8 reduces eosinophil progenitors in sputum after allergen challenge.
abstract: BACKGROUND
  TPI ASM8 contains two modified phosphorothioate antisense oligonucleotides (AON), one targeting the common beta chain (βc) of the IL-3/IL-5/GM-CSF receptors and the other targeting the chemokine receptor CCR3. Inhalation of TPI ASM8 significantly improves lung function and sputum eosinophilia after allergen inhalation challenge in asthmatics.
  
  
  OBJECTIVE
  This study assessed whether TPI ASM8 reduces airway levels of haemopoietic progenitor cells.
  
  
  METHODS
  This open-label study was conducted in 14 stable, allergic mild asthmatic subjects with early- and late-phase allergen-induced bronchoconstriction. Subjects underwent allergen challenges after 4-day treatment with placebo, 4 mg b.i.d. and 8 mg o.d. of TPI ASM8. Sputum was induced before, 7 and 24 h after allergen challenges for progenitor measurements. Treatments were separated by 2-3 weeks.
  
  
  RESULTS
  TPI ASM8 reduced allergen-induced sputum eosinophils, and the early and late asthmatic responses (P<0.05). TPI ASM8 also reduced the number of CD34(+) CCR3(+) cells (P=0.004) and CD34(+) IL-5Rα(+) cells (P=0.016), and the proportion of CD34(+) cells expressing IL-5Rα (P=0.036).
  
  
  CONCLUSIONS
  TPI ASM8 was safe and well tolerated. The results of this study demonstrate blocking of CCR3 and βc expression by TPI ASM8 significantly inhibits the accumulation of eosinophils and eosinophil progenitors in the airways after allergen challenge. Inhibition of airway progenitor cell accumulation presents a novel therapeutic target.
authors.affiliation: Department of Medicine, Division of Respirology, Neurology and Rheumatology, Kurume University School of Medicine, Kurume, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Imaoka
authors.forename: H
authors.initials: H
authors.lastname: Campbell
authors.forename: I
authors.initials: I
authors.lastname: Babirad
authors.forename: R M
authors.initials: RM
authors.lastname: Watson
authors.forename: M
authors.initials: M
authors.lastname: Mistry
authors.forename: R
authors.initials: R
authors.lastname: Sehmi
authors.forename: G M
authors.initials: GM
authors.lastname: Gauvreau
mesh_terms: D000328:Adult; D000485:Allergens / Q000008:administration & dosage / Q000276:immunology*; D018952:Antigens, CD34 / Q000378:metabolism; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology*; D001985:Bronchial Provocation Tests; D004804:Eosinophils / Q000276:immunology* / Q000378:metabolism; D005260:Female; D042381:Granulocyte Precursor Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D008297:Male; D008875:Middle Aged; D016376:Oligonucleotides, Antisense / Q000009:adverse effects / Q000627:therapeutic use*; D054735:Phosphorothioate Oligonucleotides / Q000009:adverse effects / Q000627:therapeutic use*; D013183:Sputum / Q000166:cytology / Q000276:immunology; D055815:Young Adult
chemical_list: D000485:Allergens; D018952:Antigens, CD34; D016376:Oligonucleotides, Antisense; D054735:Phosphorothioate Oligonucleotides; C559988:TPI ASM8