A newly discovered neuron-modulating agent _ glial cell-line-derived neurotrophic factor (GDNF) _ may be useful in thetreatment of Parkinson's disease and amyotrophic lateral sclerosis(ALS), also known as Lou Gehrig's disease.

Three biotechnology companies and two universities reported thepotential of GDNF in four Nature research papers. Two of theresearch groups found that GDNF reduced the amount of neuronaldegeneration seen when the axons of either dopaminergic (KlausBeck, of Genentech Inc., South San Francisco) or facial motorneurons (Qiao Yan, of Amgen Inc., Thousand Oaks, Calif.) were cut.

Similarly, Ronald Oppenheim, Bowman Gray School of Medicine, inWinston-Salem, N.C., was able to demonstrate in both mice andchickens that GDNF rescued spinal motor neurons from cell deathafter their axons were cut. This laboratory lesion simulates thedestruction in ALS of nerve cells that control muscle movement.

"Our findings suggest that GDNF or related molecules may be usefulfor the treatment of Parkinson's disease," said Beck. And Yandeclared the molecule to be "the most potent motor neuron trophicfactor found so far."

Lars Olson, of Sweden's Karolinska Institute (with input from theformer Synergen Inc., now part of Amgen), tested GDNF's protectiveand restorative effects on dopaminergic neurons in a more relevantmouse model, treated with the dopaminergic neurotoxin MPTP tomimic Parkinsonism.

"When GDNF is given after MPTP," Olson reported, "dopaminelevels and fiber density are significantly restored." He concluded thatGDNF "may have implications for the development of new treatmentstrategies for Parkinson's disease."

Regeneron Pharmaceutical Inc.'s vice-president of neurobiology,Ronald Lindsay, pointed out in his "News and Views" review of thefour Jan. 25 Nature papers that researchers at first thought GDNFcould affect very few types of neurons, due in part to its having beentested in only a few systems. "Now its specificity appears to bebroader," he wrote. "While it did not previously appear to affectsensory or sympathetic neurons, newer work indicates otherwise."

In fact, GDNF nerve-survival-promoting effects do seem to overlapin some sensory neurons with those of other neuron modulators, suchas ciliary neurotrophic factor (CNTF) and brain-derived neurotrophicfactor (BDNF). Also, Oppenheim's data suggest that GDNF doesindeed affect sympathetic, but not other, peripheral neurons, AsLindsay observed, "the more novel neurotrophic factors are explored,the more their specificity broadens."

Who Owns The Rights?

From a commercial standpoint, a striking aspect of these four papers,and the attendant Nature review, is that three biotechnologycompanies are involved. This leads to the question: What is theproprietary status of GDNF and other neurotrophic factors?

Lindsay told BioWorld Today that "GDNF appears to be the propertyof the former Synergen, now Amgen." He cautioned that "themolecule's being a member, although a distant one, of thetransforming growth factor-beta family could cause problems.

"On the other hand," Lindsay continued, "we at Regeneron feel wehave a clean situation with BDNF. Takeda [Chemical Industries Ltd.,of Osaka, Japan] has rights to neurotrophin-3, and has settled itsdispute with Amgen, Genentech and Regeneron. However,Regeneron and Synergen/Amgen are involved in an interferenceaction over CNTF. This situation," he concluded, "clearly reflects thegreat interest and competitiveness that exists today inneurobiotechnology."

Unlike earlier neurotrophic factors, such as CNTF and BDNF, whichhave similar effects on neuronal targets, GDNF is not yet in clinicaltrials. "A major clinical issue for GDNF," Lindsay pointed out, "aswith other neurotrophic factors, will be how it can be effectively andconveniently be delivered to the appropriate site in the brain. In thefinal analysis, its success will depend heavily on its therapeutic andside-effect profiles, as compared with those of CNTF and BDNF." n

-- Chester Bisbee Special To BioWorld Today

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