title: Allergen-induced asthmatic responses modified by a GATA3-specific DNAzyme.
abstract: BACKGROUND
  The 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).
  
  
  METHODS
  We 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 quantified by the change in the area under the curve (AUC) for forced expiratory volume in 1 second (FEV1).
  
  
  RESULTS
  After 28 days, SB010 attenuated the mean late asthmatic response by 34%, as compared with the baseline response, according to the AUC for FEV1, whereas placebo was associated with a 1% increase in the AUC for FEV1 (P=0.02). The early asthmatic response with SB010 was attenuated by 11% as measured by the AUC for FEV1, whereas the early response with placebo was increased by 10% (P=0.03). Inhibition of the late asthmatic response by SB010 was associated with attenuation of allergen-induced sputum eosinophilia and with lower levels of tryptase in sputum and lower plasma levels of interleukin-5. Allergen-induced levels of fractional exhaled nitric oxide and airway hyperresponsiveness to methacholine were not affected by either SB010 or placebo.
  
  
  CONCLUSIONS
  Treatment with SB010 significantly attenuated both late and early asthmatic responses after allergen provocation in patients with allergic asthma. Biomarker analysis showed an attenuation of Th2-regulated inflammatory responses. (Funded by Sterna Biologicals and the German Federal Ministry of Education and Research; ClinicalTrials.gov number, NCT01743768.).
authors.affiliation: From the Fraunhofer Institute for Toxicology and Experimental Medicine (N.K., J.M.H.) and the Department of Dermatology and Allergy, Hannover Medical School (J.Z., T.W.), Hannover, Pulmonary Research Institute at Lung Clinic Grosshansdorf, Grosshansdorf (A.-M.K.), Institut für klinische Forschung Pneumologie, Clinical Research Center Respiratory Medicine, Frankfurt (O.K.), Insaf Respiratory Research Institute, Wiesbaden (K.M.B.), Inamed, Gauting (D.K., W.T.), Pulmonary Department, Medical Clinic, University Hospital Mainz, Mainz (S.K., R.B.), Charité Research Organization, Berlin (S.I.), FGK Clinical Research, Munich (C.R.), Sterna Biologicals (J.B., U.H., A.T., J.R.) and Institute of Laboratory Medicine, Philipps University Marburg, a member of Universities Giessen and Marburg Lung Center (H.G., H.R.), Marburg - all in Germany; Upper Airways Research Laboratory, University Hospital Ghent, Ghent, Belgium (N.Z., C.B.); and the Division of Ear, Nose, and Throat Diseases, Clintec, Karolinska Institute, Stockholm (N.Z., C.B.).
authors.forename: Norbert
authors.initials: N
authors.lastname: Krug
authors.forename: Jens M
authors.initials: JM
authors.lastname: Hohlfeld
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Kirsten
authors.forename: Oliver
authors.initials: O
authors.lastname: Kornmann
authors.forename: Kai M
authors.initials: KM
authors.lastname: Beeh
authors.forename: Dominik
authors.initials: D
authors.lastname: Kappeler
authors.forename: Stephanie
authors.initials: S
authors.lastname: Korn
authors.forename: Stanislav
authors.initials: S
authors.lastname: Ignatenko
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Timmer
authors.forename: Cordelia
authors.initials: C
authors.lastname: Rogon
authors.forename: Jana
authors.initials: J
authors.lastname: Zeitvogel
authors.forename: Nan
authors.initials: N
authors.lastname: Zhang
authors.forename: Joachim
authors.initials: J
authors.lastname: Bille
authors.forename: Ursula
authors.initials: U
authors.lastname: Homburg
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Turowska
authors.forename: Claus
authors.initials: C
authors.lastname: Bachert
authors.forename: Thomas
authors.initials: T
authors.lastname: Werfel
authors.forename: Roland
authors.initials: R
authors.lastname: Buhl
authors.forename: Jonas
authors.initials: J
authors.lastname: Renz
authors.forename: Holger
authors.initials: H
authors.lastname: Garn
authors.forename: Harald
authors.initials: H
authors.lastname: Renz
mesh_terms: D000280:Administration, Inhalation; D000328:Adult; D018927:Anti-Asthmatic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D019540:Area Under Curve; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism; D015415:Biomarkers / Q000097:blood; D021881:DNA, Catalytic / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D005541:Forced Expiratory Volume; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015848:Interleukin-5 / Q000097:blood; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism*; D012260:Ribonucleases / Q000009:adverse effects / Q000627:therapeutic use*; D018418:Th2 Cells / Q000378:metabolism; D055815:Young Adult
chemical_list: D018927:Anti-Asthmatic Agents; D015415:Biomarkers; D021881:DNA, Catalytic; D050990:GATA3 Transcription Factor; D015848:Interleukin-5; D012333:RNA, Messenger; D012260:Ribonucleases; C000598349:SB010 DNAzyme