The reproductive axis is activated by gonadotropin-releasing hormone (GnRH), which stimulates the pituitary gonadotropes to secrete hormones that drive gonadal function and steroidogenesis. Thus repression of this axis, which is conserved across mammals and sexes, can reduce steroid levels and/or prevent reproduction. Steroid-dependent pathologies, including various cancers, are commonly treated with GnRH super-analogs which have long-term side-effects, while humane solutions for controlling reproduction in domestic and wild animal populations are lacking. GnRH-conjugated toxins are undergoing clinical trials for GnRHR-expressing cancer cells, and have been examined for gonadotrope ablation in animals, but showed low and/or transient effects and administration of toxins has many potential complications. Here we exploit GnRH targeting to gonadotropes to deliver DNA encoding an effector that induces gonadotropin gene repressive epigenetic modifications which are perpetuated over time. Several layers of specificity are endowed through targeting to GnRHR-expressing cells and due to local cleavage of the peptide packaging the DNA; the DNA-encoded effector is expressed and directed to the target genes by the DNA binding domain of a highly specific transcription factor. This design has multiple advantages over existing methods of shutting down the reproductive axis, and its modular design should allow adaptation for broad applications.
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This research was supported by the Office of the Chief Scientist, Ministry of Agriculture (14-16-0004), POLAK Fund for Applied Research and Hittman Family Foundation Biomedical Innovation Fund.
LP and PM are inventors on US Provisional Patent Application No. 63/221,056.
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Pnueli, L., Melamed, P. Epigenetic repression of gonadotropin gene expression via a GnRH-mediated DNA delivery system. Gene Ther 29, 294–303 (2022). https://doi.org/10.1038/s41434-022-00325-6