title: Immune activation and target organ damage are consequences of hydrodynamic treatment but not delivery of naked siRNAs in mice.
abstract: Short-interfering RNAs (siRNAs), key mediators of RNA interference comprise a promising therapeutic tool, although side effects such as interferon (IFN) response are still not perfectly understood. Further, delivery to target organs is a major challenge, possibly associated with side effects including immune activation or organ damage. We investigated whether immune activation as a consequence of double-stranded RNA induced IFN response (Jak/STAT pathway activation or cytokine production) or target organ damage is induced by in vivo low-volume (LV) or high-volume (HV) hydrodynamic delivery or treatment with naked siRNA. NMRI mice were injected with naked siRNAs or saline by hydrodynamic injection (HDI) and positive control mice received polyinosinic-polycytidilic acid (poly I:C). LV (1 mL/mouse) and HV (10% of body weight) HDI were compared. After LV HDI, STAT1 and OAS1 gene expression inflammatory cytokine plasma levels and target organ injury were assessed. LV HDI induced slight alanine aminotransferase elevation and mild hepatocyte injury, whereas HV HDI resulted in high ALAT level and extensive hepatocyte necrosis. STAT1 or OAS1 was not induced by LV siRNA; however, HV saline led to a time-dependent slight increase in gene expression. Inflammatory cytokine plasma level and organ histology and functional parameters demonstrated no damage following LV HDI with or without siRNA. Our data demonstrate that naked siRNAs may be harnessed, without the induction of IFN response or immune activation, and that LV HDI is preferable, because HV HDI may cause organ damage.
authors.affiliation: Faculty of Medicine, Institute of Pathophysiology, Semmelweis University, Nagyvárad tér 4, Budapest, Hungary.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Rácz
authors.forename: Mária
authors.initials: M
authors.lastname: Godó
authors.forename: Csaba
authors.initials: C
authors.lastname: Révész
authors.forename: Péter
authors.initials: P
authors.lastname: Hamar
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000378:metabolism; D000818:Animals; D016207:Cytokines / Q000097:blood; D015870:Gene Expression; D018014:Gene Transfer Techniques / Q000009:adverse effects*; D057446:Hydrodynamics; D007372:Interferons / Q000096:biosynthesis* / Q000235:genetics; D007668:Kidney / Q000293:injuries / Q000473:pathology; D008099:Liver / Q000293:injuries / Q000473:pathology; D008297:Male; D051379:Mice; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000009:adverse effects*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D012965:Sodium Chloride / Q000008:administration & dosage / Q000009:adverse effects; D013154:Spleen / Q000293:injuries / Q000473:pathology
chemical_list: D016207:Cytokines; D034741:RNA, Small Interfering; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D012965:Sodium Chloride; D007372:Interferons; C509914:Oas1b protein, mouse; D015088:2',5'-Oligoadenylate Synthetase