Antisense oligonucleotides on neurobehavior, respiratory, and cardiovascular function, and hERG channel current studies.
INTRODUCTION
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.


DISCUSSION
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.
['Kim|Tae-Won|TW|', 'Kim|Ki-Suk|KS|', 'Seo|Joung-Wook|JW|', 'Park|Shin-Young|SY|', 'Henry|Scott P|SP|']
D000818:Animals D001794:Blood Pressure D016466:CHO Cells D002319:Cardiovascular System D002478:Cells, Cultured D002490:Central Nervous System D003412:Cricetulus D051638:Ether-A-Go-Go Potassium Channels D005260:Female D057809:HEK293 Cells D000882:Haplorhini D006339:Heart Rate D006801:Humans D008252:Macaca fascicularis D008297:Male D051379:Mice D008813:Mice, Inbred ICR D016376:Oligonucleotides, Antisense D011323:Primates D051381:Rats D017207:Rats, Sprague-Dawley D012137:Respiratory System D013686:Telemetry
Antisense Oligonucleotide Antisense Oligonucleotide hERG hERG channel Safety pharmacology In vivo ASO Central Nervous System Methods Functional Observatory Battery CNS ECG 2′-O-methoxyethyl 2′MOE Antisense oligonucleotides Electrocardiography FOB GLP Good Laboratory Practice Human Ether-a-go-go related gene IC(50) ICH International Conference on Harmonisation LSmean Least squares mean Mean Standard Error PCO(2) PO(2) Partial pressure of CO(2) Partial pressure of O(2) Percent hemoglobin saturation S.E.M SO(2)% The half maximal inhibitory concentration