CJC-1295 DAC Peptide (5MG)

This 2006 study in the American Journal of Physiology – Endocrinology and Metabolism (Alba et al., Johns Hopkins University, with co-authors from ConjuChem) tested CJC-1295 in mice lacking the GHRH gene (GHRHKO mice). These mice have an underdeveloped pituitary, few GH-producing cells (somatotrophs) and reduced growth.

Young knockout mice received CJC-1295 at three different dosing intervals for 5 weeks. The researchers compared them with placebo-treated knockout mice and with heterozygous littermates that grow normally. They measured growth, body composition, pituitary GH and prolactin expression, pituitary histology and serum IGF-I.

Scope: This was a study in genetically modified mice. It did not test CJC-1295 in people.

• Citation: Alba M, Fintini D, Sagazio A, et al. Am J Physiol Endocrinol Metab. 2006;291(6):E1290–E1294.
• Animals: Male GHRH knockout mice (C57BL/6–SV129 background), treated from 1 week of age, plus heterozygous littermate controls
• Groups: CJC-1295 every 24 h (n = 8), every 48 h (n = 8), every 72 h (n = 7), knockout placebo (n = 8), and heterozygous placebo
• Administration in the study: Subcutaneous, for 5 weeks
• Measurements: Body weight, nose-to-anus length, femur and tibia length, lean and fat mass, pituitary RNA, GH and prolactin mRNA, GH protein, immunohistochemistry, serum IGF-I
• Disclosure: Two authors were affiliated with ConjuChem, the developer of CJC-1295.

GHRH is a 44-amino-acid hypothalamic peptide that stimulates GH release and the growth of somatotroph cells in the pituitary. Its activity comes from the 1–29 N-terminal region. Native GHRH has a very short half-life, so earlier animal studies needed repeated daily doses or infusion pumps.

In earlier work, the same group found that a potent GHRH analog given twice daily only partly corrected growth in GHRHKO mice. This study asked whether a longer-acting, albumin-binding analog could correct the growth phenotype, and how the interval between doses affected the result.

Three groups of 1-week-old GHRHKO mice received the same amount of CJC-1295 (2 µg per dose, as reported in the paper) every 24, 48 or 72 hours for 5 weeks. Placebo-treated knockout and heterozygous mice received daily vehicle. Because each group received the same amount per dose, the 48- and 72-hour groups received one-half and one-third as much in total.

At the end of treatment, mice in each group were euthanized 24, 48 or 72 hours after their last dose. The researchers then measured:

• Final body weight, nose-to-anus length, and femur and tibia length
• Lean mass, visceral fat and subcutaneous fat as a percentage of body weight
• Total pituitary RNA, GH and prolactin mRNA (Northern blot) and GH protein (Western blot)
• GH-positive cells by immunohistochemistry
• Serum IGF-I by radioimmunoassay

Every 24 hours: Knockout mice reached body weight, nose-to-anus length, and femur and tibia lengths similar to heterozygous controls.

Every 48 hours: Body weight and length were greater than in placebo knockout mice but remained below controls. Femur and tibia length were similar to controls.

Every 72 hours: Growth measures were greater than in placebo knockout mice, but none reached control levels.

Relative lean mass and subcutaneous fat mass were similar to controls in all three treated groups. Visceral fat did not differ among the five groups. The authors reported no evidence of local or systemic toxicity in the treated mice.

Compared with placebo knockout mice, total pituitary RNA rose 13-fold, 9-fold and 7-fold in the 24-, 48- and 72-hour groups. GH mRNA rose 11-fold, 8-fold and 6-fold. Adjusted for total amount given, the GH mRNA increases were similar across groups. GH protein also increased.

Immunohistochemistry showed larger pituitaries and more GH-positive cells in all treated groups. Prolactin mRNA rose much less (about 2.3–2.5-fold), and there was no clear change in prolactin-producing cell mass.

Serum IGF-I was measured at the end of each group's interval. The 24-hour group had significantly higher IGF-I than heterozygous controls. IGF-I in the 48- and 72-hour groups was not significantly different from placebo knockout mice, even though their growth measures had improved. The authors noted that similar mismatches between IGF-I and growth have been reported before.

The authors attributed the weaker effect at longer intervals to two factors. First, mouse albumin has a short half-life (about 20–24 hours), so little CJC-1295 likely remained after a day. Second, the longer-interval groups received less in total. They also suggested that body composition may respond at lower GH activity than longitudinal bone growth does.

• Groups were small (7–8 mice), all male, and treatment lasted 5 weeks in very young mice.
• The GHRH knockout mouse is a specific genetic model of GHRH deficiency.
• Albumin half-life differs between species, so the timing results are specific to mice.
• IGF-I was measured once, at a different time after the last dose in each group.
• Two authors were affiliated with the compound's developer.
• Mouse findings do not establish effects, safety or dosing in people.

Alba et al. (2006) found that CJC-1295, an albumin-binding GHRH analog, given every 24 hours for 5 weeks, brought growth measures in GHRH knockout mice to control levels and increased pituitary GH expression and GH-cell numbers. Longer intervals between doses produced partial effects on growth, while lean and subcutaneous fat proportions were similar to controls in all treated groups.

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