By Dean A. Haycock

Special To BioWorld Today

Imagine an effective medicine normally present in the brain waiting to counter the effects of stroke, trauma and a host of neurodegenerative diseases. The catch is that this endogenous medicine is normally bound to factors that inactivate it.

The standard approach to tapping the benefits of this molecule would be to inject a recombinant version of its unbound form into patients. A more novel approach would be to free the medicine by "unbinding" it.

The endogenous "medicine" is insulin-like growth factor (IGF). The unwanted constraints are proteins called insulin growth factor binding proteins (IGFBP) and the "unbinding" agent is an analog of IGF referred to as an IGFBP-ligand inhibitor. Results of preclinical experiments testing this new approach appear in the February 17, 1998, issue of The Proceedings of the National Academy of Sciences.

There are two forms of IGF, I and II. Both are important for normal growth and for development of the brain. They also are reported to protect neurons from various forms of injury. They can only do this, however, when they are not bound to one of six binding proteins, IGFBPs, which form tight associations with the growth factors.

Noting that IGFs and IGFBPs are increased following brain injury, Errol De Souza, executive vice president of research and development at Neurocrine Biosciences Inc., in San Diego, and his colleagues wondered if displacing the inactivating IGFBPs from IGFs might increase the concentration of free growth factor in the brain with resulting therapeutic benefits.

To free the endogenous IGF, the researchers used an analogue of human IGF-I, a peptide. This ligand inhibitor was chosen because it bound with high affinity to IGF-binding proteins but not to IGF receptors. It was thus suitable as a tool for freeing up unbound IGF without interfering directly with cell functions linked to IGF receptors.

Addition of the ligand inhibitor to rat cerebral spinal fluid increased the proportion of free IGF from 36 percent to 52 percent. The inhibitor also reversed the inhibitory effect of binding proteins on IGF-induced proliferation in cultured fibroblast cells. These data indicate the ligand inhibitor can free bioactive IGF from the inactivating binding proteins that normally inhibit its activity.

Next, the scientists tested the ligand inhibitor's ability to lessen brain damage following the induction of strokes in rats. Administration of the ligand inhibitor even one hour after the induction of stroke produced significant protective effects on neurons in the brain region affected by lack of blood flow.

The researchers hope to expand the window of time in which the ligand inhibitor can confer not only neuroprotective effects but, with subchronic administration over hours or a day, perhaps regenerative effects as well.

"I think this paper is potentially extremely important. Circulating IGF-I in the blood is probably relatively less important than free IGF-I. This approach has the potential of taking both IGF-I and IGF-II and maximizing their biologic activity. I think the preliminary studies in the animal experimental model have demonstrated that. Also, the in vivo model confirms that," said Michael Thorner, chairman of the department of medicine at the University of Virginia School of Medicine in Charlottesville.

Neurocrine Biosciences expects to have a development candidate within a year.

"The small molecules that we have now are in the one to three nanomolar range and show efficacy in the animal model. We just need to improve on the pharmacokinetics," De Souza said. "To the best of my knowledge, this is the first small-molecule approach to a growth factor."

A patent submitted by Neurocrine Biosciences to protect the concept and its screening approach was recently published.

"For us, this is a natural flow from one of our other projects which is related to a corticotrophin releasing factor binding protein. We have been working on this for a while but kept it under cover. At this point we have small molecules that are very much in the "drug-like" range from a standpoint of affinity and efficacy. We feel comfortable that we have a pretty good lead in this area," De Souza told BioWorld Today.

The company is now validating the approach in other disease models that include Alzheimer's and Parkinson's diseases, traumatic brain injury and multiple sclerosis.

The concept has been tested already in several models of diabetes and the authors are thinking of testing the approach in arteriosclerosis.

Proposals to use growth factors always raise the worry of inducing unwanted side effects, including uncontrolled growth of non-targeted cells.

"It has potentially great advantages because you don't flood the system. It is the endogenous hormone that is actually being made active. If you were able only to deliver it locally to an area where it was needed, then you could have specific effects at that target site," Thorner said.

Ted Dawson, associate professor of neurology and neuroscience at Johns Hopkins University School of Medicine, in Baltimore, said this would be a promising approach but points to the familiar problems of delivering growth factors and small peptides. For treating chronic disorders such as neurodegenerative disease, it will be necessary to develop an oral form of the drug.

"I truly believe this is amenable to an oral formulation," De Souza said. *