Mechanism of alternative complement pathway dysregulation by a phosphorothioate oligonucleotide in monkey and human serum.
Nucleic Acid Ther
; 24(5): 326-35, 2014 Oct.
Article
en En
| MEDLINE
| ID: mdl-25093529
ABSTRACT
The species sensitivity and mechanism of complement pathway activation by a phosphorothioate oligonucleotide were investigated in monkey and human serum. Increasing concentrations of a phosphorothioate oligonucleotide, ISIS 2302, were incubated in either monkey or human serum. Complement activation in monkey serum was selective for the alternative pathway and occurred at concentrations ≥ 50 µg/mL ISIS 2302. By comparison, complement activation in human serum was absent. A similar difference in sensitivity for activation was also observed for a representative 2'-methoxyethyl (MOE)-modified oligonucleotide. The absence of oligonucleotide-induced complement activation was also observed in dogs. Protein binding with ISIS 2302 and enzyme competition studies suggested that factor H was important in oligonucleotide-mediated complement activation process, and addition of factor H to serum effectively prevented the activation in monkey serum. Furthermore, based on the immunoassay for factor H, there was an apparent decrease in factor H concentration as the ISIS 2302 concentration increased. This result suggests that ISIS 2302 binds to factor H and interferes with the factor H antibody from the immunoassay. Factor H is a regulatory protein that limits alternative pathway activation. Disruption of factor H interaction with C3 convertase by oligonucleotide could promote activation in this pathway.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Fármacos Gastrointestinales
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Factor H de Complemento
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Activación de Complemento
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Oligodesoxirribonucleótidos Antisentido
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Oligonucleótidos Fosforotioatos
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Inmunosupresores
Límite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Nucleic Acid Ther
Año:
2014
Tipo del documento:
Article