Once-daily administration of CJC-1295, a long-acting growth hormone-releasing hormone (GHRH) analog, normalizes growth in the GHRH knockout mouse
Abstract
Although the majority of children with isolated growth hormone (GH) deficiency have a good growth response to GH-releasing hormone (GHRH), the use of this therapeutic agent is limited by its very short half-life. Indeed, we have shown that, in mice with GHRH gene ablation (GHRH knockout; GHRHKO), even twice-daily injections of a GHRH analog are unable to normalize growth. CJC-1295 is a synthetic GHRH analog that selectively and covalently binds to endogenous albumin after injection, thereby extending its half-life and duration of action. We report the effects of CJC-1295 administration in GHRHKO animals. Three groups of 1-wk-old GHRHKO mice were treated for 5 wk with 2 microg of CJC-1295 at intervals of 24, 48, and 72 h. Placebo-treated GHRHKO mice and mice heterozygous for the GHRHKO allele served as controls. GHRHKO animals receiving daily doses of CJC-1295 exhibited normal body weight and length. Mice treated every 48 and 72 h reached higher body weight and length than placebo-treated animals, without full growth normalization. Femur and tibia length remained normal in animals treated every 24 and 48 h. Relative lean mass and subcutaneous fat mass were normal in all treated groups. CJC-1295 caused an increase in total pituitary RNA and GH mRNA, suggesting that proliferation of somatotroph cells had occurred, as confirmed by immunohistochemistry images. These findings demonstrate that treatment with once-daily administration of CJC-1295 is able to maintain normal body composition and growth in GHRHKO mice. The same dose is less effective when administered every 48 or 72 h.
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MeSH terms
Aging / metabolism
Animals
Blotting, Northern
Body Composition / drug effects
Body Weight / drug effects
Bone Development / drug effects
Cell Proliferation / drug effects
Femur / drug effects
Femur / growth & development
Growth / drug effects*
Growth Hormone / deficiency*
Growth Hormone / genetics*
Growth Hormone-Releasing Hormone / analogs & derivatives*
Growth Hormone-Releasing Hormone / pharmacology
Immunohistochemistry
Mice
Mice, Inbred C57BL
Mice, Knockout
Peptide Fragments / pharmacology*
Phenotype
Pituitary Gland / drug effects
Pituitary Gland / metabolism
Prolactin / biosynthesis
RNA, Messenger / biosynthesis
Tibia / drug effects
Tibia / growth & development
Substances
CJC 1295
Peptide Fragments
RNA, Messenger
Prolactin
Growth Hormone
Growth Hormone-Releasing Hormone
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