Instead of dosing Parkinson's disease (PD) patients with L-dopa, a dopamine precursor, the discoverer of a just-reportednerve factor aims some day to rejuvenate or stimulate theaging brain cells that no longer secrete the missing neuro-transmitter.
Today's issue of Science carries a report by Frank Collins, vice-president of neuroscience at Synergen Inc. of Boulder, Colo.,under the title "A Glial Cell Line-Derived Neurotrophic Factorfor Midbrain Dopaminergic Neurons." He and his colleaguesturned an educated hunch that such a factor must exist into aprotein 134 amino acids long, which they dubbed "glia-derivedneurotrophic factor," or GDNF.
After expressing the GDNF-encoding gene in E. coli, theresearchers performed post-translational modifications torefold the protein to a bioactive configuration.
In rat embryo midbrain cell cultures, their GDNF "specificallypromoted the survival of dopaminergic neurons." And "in 20independent determinations, it caused a 2.5 to threefoldincrease in dopamine uptake per TH+, or marker, neuron." Incontrast, GDNF had no effect on uptake by the respectiveneurons of g-aminobutyric acid (GABA) or serotonin. Collinsconcluded, "GDNF is both more specific and more potent -- evenat picomolar concentrations -- than other factors that promotedopamine uptake or TH+ neuron survival in embryonicmidbrain cultures."
So much for in vitro. But how will GDNF do in vivo?
The Synergen neuroscience group is lining up animal trials oftheir new factor in rodent and simian models of PD.
As Collins told BioWorld, rats can be made to mimic thebehavioral effects of dopamine deprivation, though only up to apoint. Given a neurotoxin, which damages the brain in a waythat PD does, followed by low doses of apomorphine, adopamine look-alike molecule, rats start to turn uncontrollably.Doses of dopamine slow or stop this involuntary rotation. Sodoes Synergen's GDNF.
Simians ape human Parkinson's disease more faithfully. "Inmonkeys," Collins said, "the behavioral readout is similar towhat you'd see in a patient -- tremor, rigidity, especially in thearms." What's more, this syndrome can be quantified.
To render a rhesus monkey parkinsonian, investigators dose itwith a drug called MPTP. This neurotoxin caused a Parkinson's-like disease in drug addicts who took batches of syntheticheroine contaminated with MPTP. "They developed a diseaseessentially identical to PD," Collins recalled. His monkey trialsare just getting under way.
How about its use in human patients? Collins is cautious. "It'simportant to me that we don't make promises that areinterpreted as being guarantees of some kind of therapeuticbenefit. In that spirit, I think a neurotrophic factor like GDNFcould potentially restore function to the dopaminergic nervecells that have been damaged by the disease process. Theymight cause the remaining, still undamaged cells to sprout, andcompensate for their dysfunctional neighbors." He also foreseesthat the factor could reduce the rate of neuron degeneration,and so slow down the onslaught of the disease.
Commercial exploitation of GDGF has not escaped Synergen'snotice. A pending patent application is being published inEurope this month, Collins noted. And the company's director ofcorporate communications, Debra Catz Bannister, told BioWorldthat Synergen is negotiating to reacquire the right to GDNFfrom its neuroscience joint venture with Syntex.
Another company deeply involved in Parkinson's diseasetreatment also sees possible synergy with Synergen's GDNF. E.Edward Baetge, neuroscience director of CytoTherapeutics ofProvidence, R.I., told BioWorld that Collins' preliminary ratresponse to GDNF is "really neat!" He added, "Currently, thereare no factors out there that specifically act on dopaminergicneurons. If this is a factor that is specific for these neurons, itcould be a very important discovery in the field of Parkinson'sdisease."
But, Baetge added, "for PD therapy, how do you get this factorinto patients, past the blood-brain barrier into the centralnervous system? That's the real kicker!" To kick that kicker,Baetge imagines encapsulating Synergen's GDNF cells inCytoTherapeutics' proprietary, biocompatible, implantablemembrane.
Neurobiologist Don Gash at the University of Rochester sees "awhole series of questions that can be approached, now that thedopamine-specific factor has been found." He's sure that onceneuroscientists see GDNF's amino acid sequence, published, inthe Science paper, "a lot of groups can make probes formessenger RNA, and start doing in situ hybridization studies tolook for messenger expression." And Gash, whose field isregeneration and recovery of function in the injured brain,"declared, "This could really be a lot of fun to follow up on."
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.