CJC-1295 no DAC

This foundational study from ConjuChem characterized the tetrasubstituted hGRF(1-29) scaffold that underlies both CJC-1295 with DAC and the "no DAC" Modified GRF 1-29 used in laboratory research. The authors synthesized three maleimido derivatives of hGRF(1-29) and bioconjugated them to human serum albumin ex vivo; all three conjugates showed enhanced in vitro stability against dipeptidyl peptidase-IV (DPP-4) relative to native hGRF(1-29), and all retained bioactivity in a growth hormone secretion assay in cultured rat anterior pituitary cells. The amino-acid substitutions at positions 2 (D-Ala), 8, 15, and 27 — the same modifications present in Mod GRF 1-29 — were responsible for the protease resistance. When administered subcutaneously to male Sprague-Dawley rats, the lead compound (CJC-1295) produced a four-fold increase in GH area-under-the-curve over two hours compared with hGRF(1-29). Western blot analysis of plasma from injected rats showed a CJC-1295 immunoreactive species at the molecular weight of serum albumin, present beyond 24 hours, confirming the albumin-binding mechanism specific to the DAC variant.

Researchers built modified versions of the natural GHRH peptide by swapping four amino acids in its 29-residue core. Those same four swaps are what define Modified GRF 1-29 (CJC-1295 no DAC). In the lab, the modified peptide held up much better against the enzyme DPP-4 that normally chews up GHRH within minutes, and it still activated growth hormone-releasing receptors on pituitary cells. This study is the reference point for understanding why Mod GRF 1-29 is more stable than unmodified Sermorelin while still doing the same job at the receptor.

This multicenter open-label study examined unmodified GHRH(1-29)-NH2 (sermorelin / Geref) — the parent peptide that Mod GRF 1-29 is a stabilized analog of — in 110 previously untreated prepubertal GH-deficient children. Subjects received 30 µg/kg/day of GHRH(1-29) subcutaneously at bedtime for up to 12 months. Mean height velocity rose from 4.1 ± 0.9 cm/yr at baseline to 8.0 ± 1.5 cm/yr at 6 months and 7.2 ± 1.3 cm/yr at 12 months. At 6 months, 74% of subjects were classified as good responders. No adverse changes in general biochemical or hormonal panels were noted; fasting glucose was unchanged and no excessive generation of IGF-1 was observed. The data established that pulsatile GHRH(1-29) receptor activation at the pituitary is sufficient to drive sustained downstream GH/IGF-1 output without exogenous GH replacement — the same receptor mechanism engaged by Mod GRF 1-29.

Doctors gave a once-nightly injection of the unmodified 29-amino-acid GHRH peptide (the parent of Mod GRF 1-29) to children whose pituitaries underproduced growth hormone. Over a year, the children's growth rate roughly doubled. This was a classic demonstration that gently nudging the pituitary's GHRH receptor is enough to raise the body's own growth hormone output — without injecting growth hormone itself. Mod GRF 1-29 is studied in animal and in vitro work because it engages the same receptor, just with better stability than the parent peptide used in this trial.