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[Adverse effects of parenteral administration of antisense oligonucleotides]
1Klinika Gastroenterologii Instytutu Chorób Wewnetrznych Pomorskiej Akademii Medycznej w Szczecinie.
Abstract:
To characterize the toxicity of phosphorothioate antisense oligodeoxynucleotides ([S]ODNs) in vivo, the mice received intravenously 26-mer bcr-abl antisense oligodeoxynucleotides (1 mg/mice/day) for 9 consecutive days. The organs and tissues were removed on the indicated days (+1, +7, +30) after the treatment. Our investigation revealed middle elevation of aminotransferases activity, lactate dehydrogenase level, total protein level and globulin level, decrease of glucose, albumin and blood urea nitrogen level in the peripheral blood. The mild anaemia and thrombocytopenia were observed too. The most significant treatment-related findings in the antisense treated mice were splenomegaly, reactive hepatitis and atrocytosis of kidney. These findings together with previous results demonstrate little and temporary toxicity effects mainly in organs known from cumulating of [S]ODNs.
Insights
Phosphorothioate antisense oligodeoxynucleotides ([S]ODNs) showed mild, temporary toxicity in mice, primarily affecting the spleen, liver, and kidneys. These effects were linked to [S]ODN accumulation in specific organs.
Area of Science:
- Pharmacology
- Toxicology
- Oligonucleotide Therapeutics
Context:
- Antisense oligodeoxynucleotides (ODNs) are a promising therapeutic modality.
- Phosphorothioate modification ([S]ODN) enhances stability but can induce toxicity.
- Understanding in vivo toxicity is crucial for clinical translation.
Purpose:
- To characterize the in vivo toxicity profile of 26-mer bcr-abl antisense oligodeoxynucleotides ([S]ODNs).
- To evaluate the effects of [S]ODN treatment on various organs and blood parameters in mice.
Summary:
- Mice received daily intravenous [S]ODN injections for 9 days.
- Blood analysis revealed altered levels of liver enzymes, proteins, glucose, and blood urea nitrogen.
- Histopathological examination showed splenomegaly, reactive hepatitis, and renal atrocytosis in treated mice.
- Observed effects included mild anemia and thrombocytopenia.
Impact:
- The study demonstrates that [S]ODNs exhibit limited and transient toxicity.
- Toxicity is primarily localized to organs known for [S]ODN accumulation.
- Findings support the potential therapeutic use of [S]ODNs with careful monitoring.