Pharmacodynamics and Subchronic Toxicity in Mice and Monkeys of ISIS 388626, a Second-Generation Antisense Oligonucleotide That Targets Human Sodium Glucose Cotransporter 2
| Autor: | Thomas A. Zanardi, Scott P. Henry, Kaushik Chakravarty, Rosie Z. Yu, Su-Cheol Han, Eun Ju Jeong, Soyub Rime |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Male
endocrine system diseases Chemistry Pharmaceutical Injections Subcutaneous Renal function Pharmacology Hypoglycemia Biology Kidney Electrocardiography Mice Subcutaneous injection Sodium-Glucose Transporter 2 Diabetes mellitus medicine Animals Pharmacokinetics RNA Messenger Sodium-Glucose Transporter 2 Inhibitors Mice Inbred ICR Dose-Response Relationship Drug Hemodynamics nutritional and metabolic diseases Kidney metabolism Oligonucleotides Antisense medicine.disease Renal glucose reabsorption Macaca fascicularis medicine.anatomical_structure Oligodeoxyribonucleotides Area Under Curve Sodium/Glucose Cotransporter 2 Molecular Medicine Female Half-Life |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 343:489-496 |
| ISSN: | 1521-0103 0022-3565 |
| DOI: | 10.1124/jpet.112.197426 |
| Popis: | ISIS 388626, a 2'-methoxyethyl (MOE)-modified antisense oligonucleotide (ASO) that targets human sodium glucose cotransporter 2 (SGLT2) mRNA, is in clinical trials for the management of diabetes. SGLT2 plays a pivotal role in renal glucose reabsorption, and inhibition of SGLT2 is anticipated to reduce hyperglycemia in diabetic subjects by increasing urinary glucose elimination. To selectively inhibit SGLT2 in the kidney, ISIS 388626 was designed as a "shortmer" ASO, consisting of only 12 nucleotides with two 2'-MOE-modified nucleotides at the termini. Mice and monkeys received up to 30 mg/kg/week ISIS 388626 via subcutaneous injection for 6 or 13 weeks. Dose-dependent decreases in renal SGLT2 mRNA expression were observed, which correlated with dose-related increases in glucosuria without concomitant hypoglycemia. There were no histologic changes in the kidney attributed to SGLT2 inhibition after 6 or 13 weeks of treatment. The remaining changes observed in these studies were typical of those produced in these species by the administration of oligonucleotides, correlated with high doses of ISIS 388626, and were unrelated to the inhibition of SGLT2 expression. The kidney contained the highest concentration of ISIS 388626, and dose-dependent basophilic granule accumulation in tubular epithelial cells of the kidney, which is evidence of oligonucleotide accumulation in these cells, was the only histologic change identified. No changes in kidney function were observed. These results revealed only readily reversible changes after the administration of ISIS 388626 and support the continued investigation of the safety and efficacy of ISIS 388626 in human trials. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|