By David N. Leff

What makes organ transplantation possible is the immunosuppression that protects the alien tissues from graft rejection.

Cyclosporin A, made by Sandoz Pharmaceutical Corp., of Basel, Switzerland, is today the leading such immunosuppressant drug, but Fujisawa Pharmaceutical Co., of Osaka, Japan, has introduced a new, competing anti-rejection compound, Tacrolimus. Until recently it was known only by its research and development code name, FK-506.

Besides damping down the immune system, both of these immunophilin molecules possess a curious side effect: they also act, albeit minimally, in the nervous system. Neuroscientist Solomon Snyder of the Johns Hopkins University, in Baltimore, made this determination some seven years ago.

Snyder, who co-discovered endorphin ("the brain's own opiate") in 1976, co-founded Baltimore-based Guilford Pharmaceuticals Inc. in 1993. Since then, Guilford has taken his neurotrophic finding and run with it.

The firm's scientists dissected the double-duty FK-506 molecule into two separate parts, and developed the neurotrophic fraction into a potential drug for treating neurodegenerative afflictions, starting with Parkinson's disease. Their approach exploits Snyder's finding that these neuroactive components appear to be most active in repairing damaged neurons.

A paper in the current Proceedings of the National Academy of Sciences (PNAS), dated March 4, 1997, reports the status of their research. Its title: "Neurotrophic immunophilin ligands stimulate structural and functional recovery in neurodegenerative animal models."

Neuroscientist Peter Suzdak, Guilford's vice president of research, told BioWorld Today how he and his co-workers teased the FK-506 compound's immunological and neurological moieties apart: "We separated them by molecular modeling of FK-506's X-ray crystallographic structure. We built on earlier work elsewhere, showing that its immunity-active portion binds calcineuron, an essential enzyme on the cellular [T-cell] arm of the immune system. Its neuroactive element binds the FK-506 binding protein, but not calcineuron."

Suzdak added: "Binding the FK-506 binding protein was our initial step in this novel neurocascade, by very different pathways from the nerve growth factors."

Guilford applied structure-based drug design to step up the neuronal activity of this compound, named it GPI-1046, and checked out its effect on the neurons that sicken and die in Parkinson's disease (PD).

Orbiting PD Rats Spin One Way Only

In its most telling in vivo trial, Suzdak related, "we drilled small needle-holes in the skulls of anesthetized rats, and stereotactically microinjected a nerve toxin directly into the substantia nigra region on one side of their brains. This is the area of nerve cells that put out axons that secrete dopamine in the brain's striatum. Dopamine is the neurotransmitter depleted in PD. The toxin, in effect, gave those rats one-sided PD.

"One week later," Suzdak continued, "we followed up with subcutaneous injections of GPI-1046."

Rats are turned into animal models of Parkinson's by poisoning their substantia nigra neurons. These rodents don't display the tremors, rigidity and other symptoms of human patients. Rather they can be stimulated to rotate, spinning mindlessly around and around. The number and speed of these gyrations make it easy to measure the intensity of their disease.

Guilford's unilaterally lesioned rats rotated all right, but only in one direction — on the side of their head with dead or damaged substantia nigra nerve cells.

The rats that received GPI-1046 therapy restored the dopamine levels in their brains by one-third, compared to control animals, and their one-way spinning diminished significantly. Suzdak cited evidence that "only about a third of normal dopamine innervation is required for physiological motor activity."

An experiment in a different nerve led to an even more striking, and unexpected, payoff.

"We exposed the sciatic nerve in the legs of rats," Suzdak recounted, "crushed them with fine jewelers' forceps, then treated the lesions systemically with subcutaneous GPI-1046. Not only did the injured axons of these nerve cell bodies regenerate, but they recovered their myelin sheaths.

"We were so intrigued by this remyelination of the lesioned sciatic nerve," Suzdak observed, "that we are actively considering multiple sclerosis as another potential therapeutic target for GPI-1046."

Although initially tested subcutaneously, as reported in PNAS, GPI-1046's main claimed advantage is as an oral, rather than injectable, drug of high potency, which readily crosses the blood-brain barrier. "It's a very small, bioavailable compound," Suzdak pointed out, "with a molecular weight of only 361 * much less than the very large proteins of the various nerve growth factors now being investigated as therapeutic agents."

Guilford, he said, has repeated all its published subcutaneous tests with oral versions of the drug, and obtained similar, dose-related potency and efficacy in vivo. *