Effects of Repeated Complement Activation Associated with Chronic Treatment of Cynomolgus Monkeys with 2′-O-Methoxyethyl Modified Antisense Oligonucleotide
| Autor: | Jenna Yee, Lijiang Shen, Patricia C. Giclas, Todd Machemer, Gene Hung, John Matson, Bryan Tayefeh, Scott P. Henry, Rie Kikkawa, Jeffrey A Engelhardt |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Phosphorothioate Oligonucleotides Kidney Biochemistry Endothelial activation 03 medical and health sciences Basal (phylogenetics) Internal medicine Drug Discovery Genetics medicine Animals Humans Complement Activation Molecular Biology Dose-Response Relationship Drug Tumor Necrosis Factor-alpha business.industry Oligonucleotide Heart Oligonucleotides Antisense Immune complex Complement system Macaca fascicularis Dose–response relationship 030104 developmental biology Endocrinology medicine.anatomical_structure Liver Molecular Medicine Tumor necrosis factor alpha business |
| Zdroj: | Nucleic Acid Therapeutics. 26:236-249 |
| ISSN: | 2159-3345 2159-3337 |
| DOI: | 10.1089/nat.2015.0584 |
| Popis: | The effects of repeated complement activation in cynomolgus monkeys after chronic antisense oligonucleotide (ASO) treatment were evaluated by using ISIS 104838, a representative 2'-O-methoxyethyl (2'-MOE) modified ASO. The treatment was up to 9 months with a total weekly dose of 30 mg/kg, given either as daily [4.3 mg/kg/day, subcutaneous (s.c.) injection] or once weekly [30 mg/kg, either as s.c. injection or 30-min intravenous (i.v.) infusion]. Acute elevations of complement split products (Bb and C3a) and a transient decrease in C3 occurred after the first dose and were drug plasma concentration dependent. However, with repeated complement activation after chronic ASO treatment, there were progressive increases in basal (predose) levels of Bb and C3a, and a sustained C3 reduction in all treated groups. There was also a progressive increase in C3d-bound circulating immune complex (CIC) that was considered secondary to the C3 depletion. Evidence of vascular inflammation was observed, mostly in the liver, kidney, and heart, and correlated with severe C3 depletion and increases in plasma IgG and IgM. Vascular inflammation was accompanied by increased C3 and IgM immunereactivity in the affected vasculatures and endothelial activation markers in serum. In summary, repeated complement activations in monkeys lead to a sustained decrease in circulating C3 over time. The concomitantly increased inflammatory signals and decreased CIC clearance due to impairment of complement function may lead to vascular inflammation after chronic ASO treatment in monkeys. However, based on the known sensitivity of monkeys to ASO-induced complement activation, these findings have limited relevance to humans. |
| Databáze: | OpenAIRE |
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