By David N. Leff

Science Editor

In the days before television, when the circus rolled into town, people would gawk, among other marvels, at "the smallest human being in the world," and at "the biggest human giant."

What they were seeing, of course, was a pituitary dwarf, born with growth hormone deficiency, and an individual afflicted with acromegaly -- outsize growth caused by an excessive secretion of growth hormone.

And now for the paradox:

In both of these circus side-show exhibits, abnormal secretion of growth hormone protected their eyes from blindness caused by neovascularization -- excessive blood-vessel buildup in the retina.

Here is how pediatric ophthalmologist Lois Smith, of Harvard Medical School's Children's Hospital, in Boston, explained this counter-intuitive experiment of nature: "Human growth hormone [HGH] is a permissive factor. That's to say, if you have a sufficient amount of the hormone [which dwarfs do not], then neovascularization can go forward. And an extra amount [as in acromegaly] doesn't make that retinal angiogenesis go forward any faster."

She continued: "However, if you diminish HGH below the norm, then it appears from the experiments done in our study that you can inhibit the retinal blindness."

Today's issue of Science, dated June 13, 1997, reports Smith's experiments under the title: "Essential role of growth hormones in ischemia-induced retinal neovascularization." She presented the same new findings Wednesday in Minneapolis at the Endocrine Society's 1997 Annual Meeting.

What she and her co-authors achieved was to trace HGH's key role in a second pathway that provokes unwanted new blood vessel proliferation in the retina. Previously, she had elucidated a first pathway, featuring a different molecule, vascular endothelial growth factor (VEGF), as a candidate for therapeutic inhibition. (See BioWorld Today, May 16, 1996, p. 3.)

Retinal neovascularization afflicts more than 25 million Americans with blindness. That number includes patients with diabetic retinopathy, premature infants and -- most numerous -- elderly victims of age-related macular degeneration.

In all of these high-risk groups, the abnormal invasion of blood vessels is responding to a shortage of oxygen feeding the retina. Smith observed that "the retina is one of the most metabolically active tissues in the body. It requires a very substantial oxygen-delivery blood supply." But she pointed out that the pathogenic new vessels are very different from the normal blood conduits.

Retinal Detachment Spells Loss Of Eyesight

"The neovascular vessels," she explained, "are very leaky. Besides blood, they leak protein material that can cause scarring. The scar retracts and pulls the retina off the back of the eyeball, and this retinal detachment leads to blindness."

Smith, lead author of the Science paper, collaborated with its second author, molecular endocrinologist John Kopchick, who chairs molecular biology at Ohio University, in Athens, Ohio. He has been making mutations in the human growth hormone gene for nearly eight years.

"One of the mutations we generated," Kopchick told BioWorld Today, "turned out to convert the HGH molecule from an agonist to an antagonist. We found that if we express the agonist, which promotes HGH activity, in transgenic mice, we get big mice. An antagonist actually inhibits growth, which is how we got very small mice."

Together with Smith, Kopchick "found that the HGH antagonist will significantly reduce the vascularization of the eye."

In 1993, Ohio University licensed the antagonist in exclusivity to the Sensus Drug Development Corp., in Austin, Texas.

That company's president and CEO, John Scarlett, told BioWorld Today: "In 1994, we sublicensed similar and complementary technology from Genentech Inc., of South San Francisco. This gives Sensus an exclusive worldwide license from Genentech for all of its growth hormone antagonist technology. That's why we have," he added, "as far as we know, all the growth hormone antagonists being developed in the world under one roof, in Sensus."

Scarlett said that Sensus has "completed our preclinical program for diabetes retinopathy, and are in the process, as we speak, of designing an early Phase II clinical study."

To Prove Mechanism, Two Nails Better Than One

Endocrinologist James Schaeffer, of the Merck Research Laboratories, in Rahway, N.J., is the Science paper's final author. "We decided," Kopchick recounted, "that the growth hormone antagonist inhibited HGH activity by binding to its receptor. Merck had a compound, MK678, that did this by a completely different mechanism -- inhibiting the hormone's release from the pituitary gland. We thought if we could control the results by two different mechanisms instead of one, that would really nail down the involvement of HGH in this neovascularization process. And Schaeffer supplied us with this Merck material."

Smith's current therapeutic research in retinopathy "at present is to fine-tune the ability to control neovascularization." She explained: "The reason I put it that way is because the body also has very many processes that are beneficial, which require neovascularization. For example, wound healing, ovulation, repair of ischemic myocardium after a heart attack. Fetal development is a critical one.

"Therefore," she continued, "what I'm interested in doing is finding therapeutic solutions that are tissue-specific. I want medication that will affect the abnormal blood vessels in the eye, but not influence, say, wound healing."

She cited the latter as an example: "Let's say that wound healing might rely more on inhibition of basic fibroblast growth factor, and the retina more on growth hormone. Therefore, by fine-tuning, and giving a medication that doesn't completely inhibit any one pathway, but partially inhibits several, you might be able to get specificity."

Her current finding tracks HGH activity to its downstream effector, insulin-like growth factor-1 (IGF-1), rather than to her previous target molecule, VEGF. "What that implies," Smith suggested, "is that one might be able to modify both VEGF and IGF-1, or HGH, and achieve maximal inhibition, or more controlled inhibition, of retinal neovascularization. That is to say, by partial inhibition of these pathways, one might be able to get that specificity." *