A Combined Fertility and Developmental Toxicity Study with an Antisense Oligonucleotide Targeting Murine Apolipoprotein C-III mRNA in Mice.

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  • Additional Information
    • Source:
      Publisher: Mary Ann Liebert, Inc Country of Publication: United States NLM ID: 101562758 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2159-3345 (Electronic) Linking ISSN: 21593337 NLM ISO Abbreviation: Nucleic Acid Ther Subsets: MEDLINE
    • Publication Information:
      Original Publication: New Rochelle, N.Y. : Mary Ann Liebert, Inc.
    • Subject Terms:
      Apolipoprotein C-III*/genetics ; Apolipoprotein C-III*/antagonists & inhibitors ; Oligonucleotides, Antisense*/pharmacology ; Oligonucleotides, Antisense*/genetics ; Fertility*/drug effects ; Fertility*/genetics ; RNA, Messenger*/genetics ; RNA, Messenger*/metabolism; Animals ; Mice ; Female ; Male ; Pregnancy ; Embryonic Development/drug effects ; Embryonic Development/genetics ; Liver/drug effects ; Liver/metabolism ; Liver/pathology ; Cholesterol/metabolism
    • Abstract:
      Here, we present the reproductive toxicology profile of ISIS 838707, a GalNAc-conjugated antisense oligonucleotide (ASO) targeting mouse Apolipoprotein C-III (ApoC-III) mRNA. ISIS 838707 was subcutaneously administered during the premating, mating, and gestation periods to male and female mice at 0, 5, 10, and 20 mg/kg/week. Key focus areas included fertility, reproductive cell functions, estrus cycle, tubal transport, implantation, embryo development stages, and teratogenic potential. We also investigated the toxicokinetics and target mRNA knockdown effects. The treatment was well-tolerated at all dose levels, with no overt toxicity. Treatment led to decreased total cholesterol and/or triglyceride levels at doses ≥5 mg/kg/week, concordant with effective knockdown of ApoC-III mRNA (>85% reduction at all dose levels). Toxicokinetic analysis revealed predominant distribution to the liver of parental animals and minimally to the placenta, with no detectable transfer to fetal liver. Despite these pharmacological effects, there were no discernible adverse impacts on developmental and reproductive functions. These findings suggest that ISIS 838707, while effective in modulating ApoC-III mRNA and lipid profiles, does not adversely impact on reproductive and developmental functions in mice. The study contributes insights into the safety profile of ASOs and reduction of ApoC - III expression, particularly in the context of reproductive and developmental health.
    • Contributed Indexing:
      Keywords: ASO; ApoC-III; cardiovascular diseases; developmental and reproductive toxicology; hypertriglyceridemia
    • Accession Number:
      0 (Apolipoprotein C-III)
      0 (Oligonucleotides, Antisense)
      0 (RNA, Messenger)
      97C5T2UQ7J (Cholesterol)
    • Publication Date:
      Date Created: 20241125 Date Completed: 20241212 Latest Revision: 20241222
    • Publication Date:
      20241222
    • Accession Number:
      10.1089/nat.2024.0057
    • Accession Number:
      39585752