title: Antisense oligonucleotides on neurobehavior, respiratory, and cardiovascular function, and hERG channel current studies.
abstract: BACKGROUND
  Safety Pharmacology studies were conducted in mouse, rat, and non-human primate to determine in vivo effects of antisense oligonucleotides (ASOs) on the central nervous system, respiratory system, and cardiovascular system. Effects on the hERG potassium channel current was evaluated in vitro.
  
  
  METHODS
  ASOs contained terminal 2'-O-methoxyethyl nucleotides, central deoxy nucleotides, and a phosphorothioate backbone. Neurobehavior was evaluated by Functional Observatory Battery in rodents. Respiratory function was directly measured in rodents by plethysmograph; respiratory rate and blood gases were measured in monkey. Basic cardiovascular endpoints were measured in rat; cardiovascular evaluation in monkey involved implanted telemetry units. In single and repeat dose studies ASOs were administered by subcutaneous injection at up to 300 mg/kg, 250 mg/kg, and 40 mg/kg in mouse, rat, or monkey, respectively. Assays were performed in HEK293 or CHO-K1 cells, stably transfected with hERG cDNA, at ASO concentrations of up to 300 μM.
  
  
  RESULTS
  No apparent effects were noted for respiratory or CNS function. Continuous monitoring of the cardiovascular system in monkey demonstrated no ASO-related changes in blood pressures, heart rate, or ECG and associated parameters (i.e., QRS duration). Specific assessment of the hERG potassium channel indicated no potential for actions on ventricular repolarization or modest effects only at excessive concentrations.
  
  
  CONCLUSIONS
  The absence of direct actions on neurobehavior and respiratory function associated with the administration of ASOs in safety pharmacology core battery studies is consistent with published toxicology studies. The combination of in vitro hERG studies and in vivo studies in rat and monkey are consistent with no direct actions by ASOs on cardiac cell function or electrical conduction at relevant concentrations and dose levels. Taken as a whole, dedicated studies focused on the safety pharmacology of specific organ systems do not appear to add significant data for interpretation of potential adverse effects. The need for dedicated studies for future ASOs in the same class is questionable, as a more encompassing data set can be collected in repeat dose and longer-term toxicology studies.
authors.affiliation: Isis Pharmaceuticals, Inc., 2855 Gazelle Ct., Carlsbad, CA 92010, USA. Electronic address: tkim@isisph.com.
authors.forename: Tae-Won
authors.initials: TW
authors.lastname: Kim
authors.affiliation: Korea Institute of Toxicology, Korea Research Institute of Chemical Technology, Yuseong, Daejeon 305-600, Republic of Korea.
authors.forename: Ki-Suk
authors.initials: KS
authors.lastname: Kim
authors.affiliation: Korea Institute of Toxicology, Korea Research Institute of Chemical Technology, Yuseong, Daejeon 305-600, Republic of Korea.
authors.forename: Joung-Wook
authors.initials: JW
authors.lastname: Seo
authors.affiliation: Korea Institute of Toxicology, Korea Research Institute of Chemical Technology, Yuseong, Daejeon 305-600, Republic of Korea.
authors.forename: Shin-Young
authors.initials: SY
authors.lastname: Park
authors.affiliation: Isis Pharmaceuticals, Inc., 2855 Gazelle Ct., Carlsbad, CA 92010, USA.
authors.forename: Scott P
authors.initials: SP
authors.lastname: Henry
mesh_terms: D000818:Animals; D001794:Blood Pressure; D016466:CHO Cells; D002319:Cardiovascular System / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism; D003412:Cricetulus; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism*; D005260:Female; D057809:HEK293 Cells; D000882:Haplorhini; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D016376:Oligonucleotides, Antisense / Q000009:adverse effects* / Q000235:genetics / Q000494:pharmacology*; D011323:Primates; D051381:Rats; D017207:Rats, Sprague-Dawley; D012137:Respiratory System / Q000187:drug effects* / Q000378:metabolism; D013686:Telemetry / Q000379:methods
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D016376:Oligonucleotides, Antisense
keywords: 2′-O-methoxyethyl; 2′MOE; ASO; Antisense Oligonucleotide; Antisense oligonucleotides; CNS; Central Nervous System; ECG; Electrocardiography; FOB; Functional Observatory Battery; GLP; Good Laboratory Practice; Human Ether-a-go-go related gene; IC(50); ICH; In vivo; International Conference on Harmonisation; LSmean; Least squares mean; Mean Standard Error; Methods; PCO(2); PO(2); Partial pressure of CO(2); Partial pressure of O(2); Percent hemoglobin saturation; S.E.M; SO(2)%; Safety pharmacology; The half maximal inhibitory concentration; hERG; hERG channel