title: Toxicity profile of the GATA-3-specific DNAzyme hgd40 after inhalation exposure.
abstract: DNAzymes are single-stranded catalytic DNA molecules that bind and cleave specific sequences in a target mRNA molecule. Their potential as novel therapeutic agents has been demonstrated in a variety of disease models. However, no studies have yet addressed their toxicology and safety pharmacology profiles in detail. Here we describe a detailed toxicological analysis of inhaled hgd40, a GATA-3-specific DNAzyme designed for the treatment of allergic bronchial asthma. Subacute toxicity, immunotoxicity, and respiratory, cardiovascular, and CNS safety pharmacology were analyzed in rodents and non-rodents, and genotoxicity was assessed in human peripheral blood. Overall, hgd40 was very well tolerated when delivered by aerosol inhalation or slow intravenous infusion. Only marginal reversible histopathological changes were observed in the lungs of rats receiving the highest dose of inhaled hgd40. The changes consisted of slight mononuclear cell infiltration and alveolar histiocytosis, and moderate hyperplasia of bronchus-associated lymphoid tissue. No local or systemic adverse effects were observed in dogs. No compound-related respiratory, cardiovascular, or CNS adverse events were observed. The only relevant immunological findings were very slight dose-dependent changes in interleukin-10 and interferon-γ levels in bronchoalveolar lavage fluid. Taken together, these results support direct delivery of a DNAzyme via inhalation for the treatment of respiratory disease.
authors.affiliation: Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hannover, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Fuhst
authors.forename: Frank
authors.initials: F
authors.lastname: Runge
authors.forename: Jochen
authors.initials: J
authors.lastname: Buschmann
authors.forename: Heinrich
authors.initials: H
authors.lastname: Ernst
authors.forename: Christiane
authors.initials: C
authors.lastname: Praechter
authors.forename: Tanja
authors.initials: T
authors.lastname: Hansen
authors.forename: Jasmin
authors.initials: J
authors.lastname: von Erichsen
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Turowska
authors.forename: Heinz-Gerd
authors.initials: HG
authors.lastname: Hoymann
authors.forename: Meike
authors.initials: M
authors.lastname: Müller
authors.forename: Gerhard
authors.initials: G
authors.lastname: Pohlmann
authors.forename: Katherina
authors.initials: K
authors.lastname: Sewald
authors.forename: Christina
authors.initials: C
authors.lastname: Ziemann
authors.forename: Gerhard
authors.initials: G
authors.lastname: Schlüter
authors.forename: Holger
authors.initials: H
authors.lastname: Garn
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D001921:Brain / Q000187:drug effects; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D021881:DNA, Catalytic / Q000008:administration & dosage / Q000633:toxicity*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D050990:GATA3 Transcription Factor / Q000235:genetics*; D006321:Heart / Q000187:drug effects; D007371:Interferon-gamma / Q000032:analysis; D016753:Interleukin-10 / Q000032:analysis; D008168:Lung / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D008297:Male; D051381:Rats; D017208:Rats, Wistar
chemical_list: D021881:DNA, Catalytic; D050990:GATA3 Transcription Factor; C583023:Hgd40 DNAzyme; D016753:Interleukin-10; D007371:Interferon-gamma