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Research ArticleToxicology

Pharmacodynamics and Subchronic Toxicity in Mice and Monkeys of ISIS 388626, a Second-Generation Antisense Oligonucleotide That Targets Human Sodium Glucose Cotransporter 2

Thomas A. Zanardi, Su-Cheol Han, Eun Ju Jeong, Soyub Rime, Rosie Z. Yu, Kaushik Chakravarty and Scott P. Henry
Journal of Pharmacology and Experimental Therapeutics November 2012, 343 (2) 489-496; DOI: https://doi.org/10.1124/jpet.112.197426
Thomas A. Zanardi
Isis Pharmaceuticals, Carlsbad, California (T.A.Z., R.Z.Y., K.C., S.P.H.); and Korea Institute of Toxicology, Daejeon, Republic of Korea (S.-C.H., E.J.J., S.R.)
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Su-Cheol Han
Isis Pharmaceuticals, Carlsbad, California (T.A.Z., R.Z.Y., K.C., S.P.H.); and Korea Institute of Toxicology, Daejeon, Republic of Korea (S.-C.H., E.J.J., S.R.)
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Eun Ju Jeong
Isis Pharmaceuticals, Carlsbad, California (T.A.Z., R.Z.Y., K.C., S.P.H.); and Korea Institute of Toxicology, Daejeon, Republic of Korea (S.-C.H., E.J.J., S.R.)
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Soyub Rime
Isis Pharmaceuticals, Carlsbad, California (T.A.Z., R.Z.Y., K.C., S.P.H.); and Korea Institute of Toxicology, Daejeon, Republic of Korea (S.-C.H., E.J.J., S.R.)
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Rosie Z. Yu
Isis Pharmaceuticals, Carlsbad, California (T.A.Z., R.Z.Y., K.C., S.P.H.); and Korea Institute of Toxicology, Daejeon, Republic of Korea (S.-C.H., E.J.J., S.R.)
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Kaushik Chakravarty
Isis Pharmaceuticals, Carlsbad, California (T.A.Z., R.Z.Y., K.C., S.P.H.); and Korea Institute of Toxicology, Daejeon, Republic of Korea (S.-C.H., E.J.J., S.R.)
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Scott P. Henry
Isis Pharmaceuticals, Carlsbad, California (T.A.Z., R.Z.Y., K.C., S.P.H.); and Korea Institute of Toxicology, Daejeon, Republic of Korea (S.-C.H., E.J.J., S.R.)
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Abstract

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.

Footnotes

  • Financial support for this project was provided by Isis Pharmaceuticals, Inc.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.112.197426.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    SGLT
    sodium glucose cotransporter
    ASO
    antisense oligonucleotide
    MOE
    methoxyethyl
    KIT
    Korea Institute of Toxicology
    BLQ
    below the lower limit of quantitation
    AUC
    area under the curve
    CV
    coefficient of variation.

  • Received July 9, 2012.
  • Accepted August 20, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 343 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 343, Issue 2
1 Nov 2012
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Research ArticleToxicology

Inhibition of SGLT2 by ISIS 388626 in Mice and Monkeys

Thomas A. Zanardi, Su-Cheol Han, Eun Ju Jeong, Soyub Rime, Rosie Z. Yu, Kaushik Chakravarty and Scott P. Henry
Journal of Pharmacology and Experimental Therapeutics November 1, 2012, 343 (2) 489-496; DOI: https://doi.org/10.1124/jpet.112.197426

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Research ArticleToxicology

Inhibition of SGLT2 by ISIS 388626 in Mice and Monkeys

Thomas A. Zanardi, Su-Cheol Han, Eun Ju Jeong, Soyub Rime, Rosie Z. Yu, Kaushik Chakravarty and Scott P. Henry
Journal of Pharmacology and Experimental Therapeutics November 1, 2012, 343 (2) 489-496; DOI: https://doi.org/10.1124/jpet.112.197426
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