A four-year, 22-scientist, trans-Atlantic task force has createda recombinant protein with potential for regenerating damagedperipheral nerves and treating degenerative neuropathies.
Their discovery is the lead article in today's Nature, "Glialgrowth factors are alternatively spliced erbB2 ligandsexpressed in the nervous system." The implications of thediscovery moved the editors of Nature to accept the paper forpublication a mere three weeks after Cambridge NeuroScienceInc. (NASDAQ:CNSI) of Cambridge, Mass., submitted it Feb. 4.(Nature's average time-lapse between submission andacceptance is about 15 weeks.)
Glial cells of various kinds are found in the gray and whitematter of brain and spinal cord, the central nervous system(CNS). In the peripheral nerve network -- notably, arms andlegs -- Schwann cells are the only glial type on duty. Duringembryonic growth and nerve-injury repair, Schwann cellsmark in advance the trail along which neurons grow out andbranch off from the spinal cord. They then wrap the developingaxons in a myelin sheath, which promotes conductance ofmessages along the nerve pathways.
Missing myelination in the CNS is the hallmark of multiplesclerosis, and "Schwann cells run amok are a feature ofneurofibromatosis -- erroneously termed 'elephant man'sdisease,' " said Robert McBurney, Cambridge Neuro's vicepresident of research.
After a decade of exquisite protein purification, bioassay andanalysis, which consumed tens of thousands of bovine pituitaryglands, Britain's prestigious Ludwig Institute for CancerResearch isolated the gene for glial growth factor (GGF), theprotein that activates Schwann cells to do their jobs of nervedevelopment and myelination. Then Cambridge Neuro, withinput from a Columbia University histochemist, deployed thegamut of molecular genetic technologies to synthesize andexpress the gene for human GGF, initially in primate COS cells.
Part of this DNA sequence was already known, particularly inrecently published work by Genentech Inc. and Amgen Inc.investigators, as the ligand for an oncogene, erbB2, of whichmutants are suspected of causing multiple tumors in laboratoryrats.
"Even though other products of the same gene have beenidentified by Genentech and Amgen," said McBurney, "there issufficient uniqueness about the product we have produced,particularly the fact that, thanks to an N-terminus we andLudwig discovered, it is secreted from cells, and can be readilyharvested from the medium."
He pointed out that "strangely enough, these projects oftencome down to how easy the protein is to make in good yield."
Because this multifaceted gene, a member of the epithelialgrowth factor family, engages in alternative messenger RNAsplicing, it can encode numerous versions of the GGF protein.After confirming in vitro its efficacy in activating Schwanncells, Cambridge Neuro scientists are now beginning in vivoexperiments in rats.
As molecular neurobiologist Mark A. Marchionni, first authoron the Nature paper, described this work to BioWorld: "We cutthe sciatic nerve and remove a known length. Next, we connectthe ends to a little tube containing glial growth factor. Thenerve then grows and connects. We hope our approach willaccelerate this process. In untreated rats, it takes about twomonths of spontaneous regeneration to repair a severed nerve,and complete function is not usually restored."
For now the team is focusing on peripheral nerve therapy, butGGF should also work on central nervous system glial cells."Treating cerebral injuries," Marchionni explained, "wouldinvolve getting the protein across the blood-brain barrier,which is why these therapies are on our back burner. But," headded, "we expect to begin in vitro studies of CNS cells withinabout six months."
Preliminary human trials of peripheral cells, McBurney hopes,will get under way before the end of 1994. "Our time scale atthe moment is that it will take at least 18 months before wewould have clinical-grade material for human trials."
"Many of these neuronal ligands are coming out from manydifferent sources," said molecular neurobiologist George D.Yancopoulos, vice president for discovery at RegeneronPharmaceuticals Inc., which is developing therapies for nervedisorders. Regeneron has a ciliary neurotrophic factor in clinicaltrials for treating amyotrophic lateral sclerosis (Lou Gehrigdisease). For now, the Tarrytown, N.Y., company(NASDAQ:REGN) is concentrating on degenerative neuropathies,not trauma.
Rather than comment on Cambridge Neuro's newly announcedglial growth factor gene until he has read the Nature paper,Yancopoulos cited the generic caveats that arise in groomingthe current influx of nerve growth factors for human use:
"Many of these ligands," he told BioWorld., "have cross-reactivespecificities on a variety of receptors that are expressed both inand out of the nervous system, on neurons as well as onproliferating cells.
"There will certainly be major questions as to their specificitiesin vivo -- specifically, whether they are going to be specific topost-mitotic neurons, or whether they'll have growth actions onmitotically active cells. For the latter, you wouldn't want toinduce proliferation, which can have deleterious effects ofcellular overgrowth."
-- David N. Leff Science Editor
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