Every one of the kerzillion cells in a human body is living onborrowed time. Interest payments on these cellular loans take theform of signals from neighboring growth factors or hormones thatkeep the cell alive. If a cell defaults on its mortgage installment,apoptosis _ programmed cell death _ removes it from the scene.

This cell-survival theory motivates molecular biologists to trackdown the receptor molecules by which the life-preserving messagesget through to the cell.

One such specialized signal generator is glial-cell-line-derivedneurotrophic factor (GDNF). Discovered in 1993 by Frank Collins,vice president of Synergen Inc., GDNF proved in vitro to protectsurvival of the midbrain cells that secrete dopamine. It's therelentless, age-related, loss of these dopaminergic neurons that bringson Parkinson's disease (PD).

When Amgen Inc., of Thousand Oaks, Calif., acquired Synergen Inc.,of Boulder, Colo., in late 1994, (see BioWorld Today, March 21,1996, p. 1) it inherited a dominant patent position coveringrecombinant GDNF. The company will conduct Phase I clinical trialsof the nerve factor "sometime this summer," the company'sspokeswoman Lynne Connell said.

"If we grow dopaminergic neurons in a test tube without GDNF,"said molecular neurobiologist Arnon Rosenthal, of Genentech Inc.,"they die within 24 hours. With the correct factors, the cells wouldsurvive for a very long time."

Like many other neuroscientists in this field, Rosenthal and hislaboratory co-workers set out to find the receptor by which GDNFtransmitted its hang-in-there message to those neurons. A paper in thecurrent issue of Nature, dated July 4, 1996, reports his discoveryunder the title: "Characterization of a multicomponent receptor forGDNF."

"The important thing there," Rosenthal told BioWorld Today, "is thatfor the first time we found the physiological function of a gene that,when mutated, was known for the last 10 years to cause thyroidcancer." He added, "This oncogene being C-Ret."

C-Ret, he explained, turned out to be one of the two proteins thatcompose the receptor for GDNF. "Now that we know how itsoncogene works," he observed, "we may be able to come up withnew therapy for thyroid tumor."

One Mystery Down, One To Go

The second unknown that Rosenthal's group probed _ as did at leasttwo other teams _ was what that GDNF growth factor's function isin mammalian reproduction and on into adult life. Three other papersin that same July 4th issue of Nature tackled the question: What isthis factor doing in a normal animal?

All three, working separately, began by constructing highly abnormaltransgenic mice _ bereft of the gene expressing GDNF. Theirrespective reports in Nature tell the same story, with strikingly similartitles:

* "Renal and neuronal abnormalities in mice lacking GDNF," wroteRosenthal and his co-authors.

* "Renal agenesis and the absence of enteric neurons in mice lackingGDNF," from Mariano Barbacid's team at Bristol-Myers SquibbPharmaceutical Research Institute, of Princeton, N.J.

* "Defects in enteric innervation and kidney development in micelacking GDNF," by Heiner Westphal and associates at NIH'sLaboratory of Mammalian Genes and Development, of Bethesda,Md.

Rosenthal deems these concordant results "quite surprising. Whateach of us found," he said, "was that GDNF is in fact a kidney growthfactor, not a survival factor for dopaminergic neurons."

But he cited an alternative explanation: "The transgenic mice thatdon't have GDNF lack kidneys, and die one day after they are born.It's possible that GDNF is an important physiological survival factorfor dopaminergic neurons in adults, or at later stages in development.We weren't able to detect that because the mice died too early."

Genentech, he continued, "now is contemplating using a gene-targeting technique to get around the Catch-22 of looking for thefactor in mice who don't have its gene. This enzyme-based method,"he said, "allows you to remove or inactivate a gene at any age or inany given tissue, during gestation and even in adult life. It will permittesting the dopaminergic growth-factor capability of GDNF."

Besides inducing the embryonic ureteric bud to create kidneys,Rosenthal went on, "the second major function of GDNF isdevelopment of the nervous system in the gut, where it controlsperistaltic movement. These two findings," he observed, "may havetherapeutic implications, both in kidney failure and in diseases of thegastrointestinal tract."

Three Therapies For Parkinson's

Such medical indications figure in Genentech's research anddevelopment program, but treatments for Parkinson's disease topRosenthal's agenda. "That's how we got into GDNF," he remarked,and described three therapeutic approaches to counter "the problemin PD that these dopaminergic neurons degenerate and die:"

* Enhancement: "This is current therapy _ giving the patient L-dopa, an analogue of dopamine which gets incorporated into the still-surviving neurons. These then secrete more dopamine than untreatedcells would, thus enhancing their function, and compensating for theirsmaller number. But," he pointed out, "PD is a progressive disease,and as more and more neurons die, this treatment is no longereffective."

* Transplantation: "So far, this has been done with cells from humanembryos, an approach that is not really practical, and morallyproblematic. We are trying to develop a system for growing aninfinite number of the dopaminergic neurons in vitro, andtransplanting these. We start with one line of human fetal neurons,find conditions where we can expand the stem cells, then induce themto differentiate into dopaminergic lineages."

* Prevention: "In this approach," Rosenthal said, "we will try toprevent the death of the dopaminergic neurons in the PD patient, by aform of gene therapy to express GDNF or its homologue in thepatient's brain."

He concluded: "There is hope in neurotrophic factors, GDNF orothers, for treating such neurodegenerative disorders as Parkinson'sdisease, amyotrophic lateral sclerosis, muscular dystrophy, chronicdiabetic pain and Alzheimer's disease." n

-- David N. Leff Science Editor

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

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