Recombinant growth hormone has been adding inches to the heightof short-stature children since the early 1980s. Yet, paradoxically,from two-thirds to three-fourths of these linearly challengedyoungsters are making some of their own growth hormone.

What's the catch? Growth hormone (GH) is secreted in the pituitarygland, but released by the brain's hypothalamus. In most patientstreated with growth hormone, writes endocrine oncologist AndrewSchally, "GH insufficiency is due to changes in the control of GHsecretion by the hypothalamus, rather than to an impairment at thepituitary level. Thus, an alternative form of therapy based on thehuman hypothalamic growth hormone-releasing hormone (hGH-RH)that stimulates GH secretion could also be used."

Schally, a Nobelist who heads experimental medicine at TulaneUniversity, in New Orleans, put forward this suggestion in the currentProceedings of the National Academy of Sciences (PNAS), datedMay 23. In a paper titled "Synthesis and biological evaluation ofsuperactive agonists of growth-hormone-releasing hormone," hedescribed analogs of GH-RH, some "with 100 to 200 times thepotency" of the native thalamic hormone.

The business end of hGH-RH, its smallest active fragment, is 29amino acids long, and not always outstandingly efficient. Schally andhis co-authors synthesized a series of nine agonistic analogs to bindGH competitively, and with greater activity and stability.

By substituting amino acids at various sites along the peptide chain,they protected GH-RH from its tendency to break down rapidly underproteolytic enzyme attack, and metabolize too rapidly. Thisprolonged the hormone's half-life, enhancing its effectiveness infreeing GH.

"Of course," Schally told BioWorld Today, "the prerequisite for theresponse is that the pituitary contains some GH. If it does, then GH-RH, or our analogs, will liberate it."

His initial molecular mimics of hGH-RH's 1-29 sequence, like thoseof other laboratories, lacked enough potency. "Finally," he said, "Iand my first author, Jan Izdebski, managed to make what I feel arethe most active agonistic analogs of GHRH produced so far."

He sees four applications for these analogs: "To stimulate growth inpituitary dwarfs; for extremely short pituitary-deficient children; torestore loss of muscle in geriatric patients; to stimulate milkproduction in cows and sheep."

On this veterinary score, Schally notes that "The Australians, NewZealanders and also Argentineans are interested." For humanpatients, he deplores the high cost of treatment, "Recombinant growthhormone therapy is prohibitively expensive," Schally observed. "Itmay cost $25,000 a year for a child."

Genentech press spokesman Jim Weiss told BioWorld that theaverage cost to treat a child runs $18,000 a year, with therapy usuallycontinuing five to 10 years. "You can add anywhere from 7 inches toa foot," he said, and pointed out that "Genentech supplies our drugthrough an uninsured-patient program. We've probably given awayabout $130 million of free growth hormone since it's been on themarket." Of 20,000 children who need the drug, he said, 18,000 arereceiving it.

Weiss estimated the market for human GH at "somewhere over $300million, of which Genentech did $224 million last year."

Schally believes that a clinically acceptable releasing-hormoneanalog might have a price tag one-tenth that of recombinant humanGH. "We are now hoping to start toxicology and clinical studies," hesaid, "but Tulane University has so far not decided on commercialdevelopment of our pending patents." He added, "Several firms areinterested, but they have not yet signed the agreements or selected apartner."

In initial in vitro trials of their synthetic agonists, the PNAS paperreports, "All analogs were found to have higher binding affinities forGH-RH receptors on rat pituitary cells than hGH-RH-(1-29)-NH2."

After successfully proving their analogs in vitro, the Tulaneendocrinologists injected them intravenously and subcutaneously intoliving rodents. "These in vivo measurements," Schally concluded,"gave clear indication of very high activity, 100 to 200 times morepotent than the original 1-29 amino-acid hGH-RH." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.

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