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1.
Respir Res ; 19(1): 55, 2018 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-29615049

RESUMO

BACKGROUND: A subset of COPD-patients presents with eosinophilic airway inflammation. While treatment of asthmatic patients with the GATA3-specific DNAzyme SB010 attenuated sputum eosinophilia after allergen challenge, this specific treatment has not been evaluated in patients with COPD. Our objective was to evaluate the feasibility and safety of inhaled SB010 in COPD patients with sputum eosinophilia. METHODS: We conducted a randomized, double-blind, placebo-controlled, multicentre clinical trial in COPD-patients with sputum eosinophilia (≥2.5% non-squamous cells). Patients inhaled 10 mg SB010 bid or matching placebo via the controlled inhalation system AKITA2 APIXNEB for 28 days. Endpoints included the feasibility of the study (primary), patient's safety, sputum eosinophils, FENO, lung function, symptoms, and biomarkers. The study was registered in the German Clinical Trials Register: DRKS00006087. RESULTS: One hundred thirty patients were screened, 23 patients were randomized (FEV1 49.4 ± 11.5%; sputum eosinophils 8.0 ± 8.4%) and 19 patients completed the study (10 placebo, 9 SB010. After 28 days, SB010 decreased the relative sputum eosinophil count (p = 0.004) as compared to no changes in placebo-treated patients. FENO, lung function, and symptoms were not affected significantly. We found an increase in blood IFN-γ (p = 0.02) and a trend to lower IL-5 levels in patients treated with SB010. SB010 was safe and well tolerated. Thirty five AEs (22 SB010, 13 placebo including 1 SAE) were observed with 3 AEs in each group judged to be possibly treatment-related. CONCLUSION: In patients with eosinophilic COPD, sputum eosinophils could be reduced by inhalation of SB010. Long-term studies are needed to demonstrate clinical efficacy.


Assuntos
DNA Catalítico/administração & dosagem , Eosinófilos/metabolismo , Fator de Transcrição GATA3/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Eosinofilia Pulmonar/tratamento farmacológico , Escarro/metabolismo , Administração por Inalação , Idoso , Método Duplo-Cego , Eosinófilos/efeitos dos fármacos , Eosinófilos/patologia , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/metabolismo , Eosinofilia Pulmonar/diagnóstico , Eosinofilia Pulmonar/metabolismo , Escarro/efeitos dos fármacos
2.
N Engl J Med ; 372(21): 1987-95, 2015 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-25981191

RESUMO

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.).


Assuntos
Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , DNA Catalítico/uso terapêutico , Fator de Transcrição GATA3/metabolismo , RNA Mensageiro/metabolismo , Ribonucleases/uso terapêutico , Administração por Inalação , Adulto , Antiasmáticos/efeitos adversos , Área Sob a Curva , Asma/metabolismo , Biomarcadores/sangue , DNA Catalítico/efeitos adversos , Método Duplo-Cego , Volume Expiratório Forçado , Fator de Transcrição GATA3/genética , Humanos , Interleucina-5/sangue , Masculino , Pessoa de Meia-Idade , Fenótipo , Ribonucleases/efeitos adversos , Células Th2/metabolismo , Adulto Jovem
4.
Toxicol Appl Pharmacol ; 272(2): 365-72, 2013 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-23820074

RESUMO

The DNAzyme hgd40 was shown to effectively reduce expression of the transcription factor GATA-3 RNA which plays an important role in the regulation of Th2-mediated immune mechanisms such as in allergic bronchial asthma. However, uptake, biodistribution and pharmacokinetics of hgd40 have not been investigated yet. We examined local and systemic distribution of hgd40 in naive mice and mice suffering from experimental asthma. Furthermore, we evaluated the pharmacokinetics as a function of dose following single and repeated administration in rats and dogs. Using intranasal administration of fluorescently labeled hgd40 we demonstrated that the DNAzyme was evenly distributed in inflamed asthmatic mouse lungs within minutes after single dose application. Systemic distribution was investigated in mice using radioactive labeled hgd40. After intratracheal application, highest amounts of hgd40 were detected in the lungs. High amounts were also detected in the bladder indicating urinary excretion as a major elimination pathway. In serum, low systemic hgd40 levels were detected already at 5 min post application (p.a.), subsequently decreasing over time to non-detectable levels at 2h p.a. As revealed by Single Photon Emission Computed Tomography, trace amounts of hgd40 were detectable in lungs up to 7 days p.a. Also in the toxicologically relevant rats and dogs, hgd40 was detectable in blood only shortly after inhalative application. The plasma pharmacokinetic profile was dose and time dependent. Repeated administration did not lead to drug accumulation in plasma of dogs and rats. These pharmacokinetic of hgd40 provide guidance for clinical development, and support an infrequent and convenient dose administration regimen.


Assuntos
Antiasmáticos/farmacocinética , DNA Catalítico/farmacocinética , Fator de Transcrição GATA3/metabolismo , Administração por Inalação , Animais , Antiasmáticos/administração & dosagem , Antiasmáticos/sangue , Asma/tratamento farmacológico , Asma/metabolismo , DNA Catalítico/administração & dosagem , DNA Catalítico/sangue , Cães , Feminino , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Confocal , Ratos , Ratos Wistar , Especificidade da Espécie , Distribuição Tecidual
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