Type II Gonadotropin-Releasing Hormone Receptor and Gonadotropin-Releasing Hormone - III from Lamprey

Endocrinology

Inventors at the University of New Hampshire have cloned GnRH-III and a type II GnRH Receptor from lamprey (an eel-like fish model organism).Lamprey GnRH-III stimulates release of FSH, but not LH, which makes it a useful tool for studying and developing novel GnRH analogs that can modulate the reproductive cycle (and sex hormone synthesis).

Project Team

Prof. Stacia Sower
Prof. Stacia Sower

Institutions

University of New Hampshire
University of New Hampshire
US

Project Status

Clinical Stage
Preclinical
Patent Status
Patent not filed

Funding Opportunity

Opportunity type
Funding requested
$0
Funding allocated
$0

Background

Gonadotropin Releasing Hormone (GnRH) analogs are a billion dollar industry, with individual drugs reaching blockbuster status. For example, sales of Lupron Depot® (AbbVie) in 2015 were over $800 million. These analogs are used therapeutically for the treatment of hormone-responsive cancers like prostate cancer, and for uterine diseases like endometriosis. They are also used to regulate conception (primarily for timed ovulation during in vitro fertilization) for humans and livestock. The GnRH sequence (a ten amino acid peptide) was determined in 1971 and has been the object of continued intense study. Binding of GnRH to its cognate receptors in the pituitary stimulates release of lutenizing hormone (LH) and follicle-stimulating hormone (FSH), which in turn travel through the bloodstream to the gonads, where they stimulate gametogeneis. There are two isoforms of GnRH: GnRH-I is present in the hypothalamus and acts on the pituitary, while GnRH-II is outside the hypothalamus and might not be involved with gonadotropin regulation at all. The two isoforms differ slightly in their amino acid sequence. Over the years, experimental substitutions of each amino acid position has not only helped define the peptide/receptor binding interaction, but also has led to the development of analogs with increased potency and half-life, and are currently high volume drugs. The GnRH-Receptor is a GPCR with two isoforms itself. The Type II form has a highly conserved intracellular tail that is vital for G-protein coupling, while the Type I form is tail-less. The difference between the two could help explain (and modulate) undesirable side effects of GnRH analogs. Existing GnRH analogshave been useful enough to generate billions of dollars in sales, but are far from optimal. As peptides, they are not orally available and need to be injected. Side effects can also be extreme, such as the testosterone and estrogen depleting effects of leuprolide, one of the most popular GnRH agonists.

Project Details

Inventors at the University of New Hampshire have cloned GnRH-III and a type II GnRH Receptor from lamprey (an eel-like fish model organism).Lamprey GnRH-III stimulates release of FSH, but not LH, which makes it a useful tool for studying and developing novel GnRH analogs that can modulate the reproductive cycle (and sex hormone synthesis).