Regeneron Pharmaceuticals Inc. is collaborating to develop aunique molecule that could have therapeutic applications inneurodegenerative diseases.
"Noggin looks like it's going to be defining a whole new class ofmolecule," said George Yancopoulos, vice president of discoveryresearch at Regeneron. Among its obvious therapeuticindications are Parkinson's, Alzheimer's, amyothrophic lateralsclerosis (ALS) and spinal-cord injuries, he told BioWorld.
Regeneron developed the elusive noggin molecule in closecollaboration with Richard Harland and his team ofdevelopmental biologists at the University of California,Berkeley (UCB), who discovered the molecule. Yancopoulos andHarland are the principal co-authors of a report in last week'sissue of Science titled "Neural Induction by the SecretedPolypeptide Noggin."
Regeneron (NASDAQ:REGN) of Tarrytown, N.Y., holds anexclusive worldwide option to license the basic patent filed byUCB covering the eventual uses of noggin.
Graduate student Teresa Lamb, lead author on the Sciencepaper, told BioWorld that high-dose injections of noggin RNAinto amphibian embryos caused them to have larger thannormal head structure, hence the name noggin.
The amphibian embryos come from Xenopus laevis, the Africanclawed frog, a favorite model of developmental biologists. Earlyin this century German embryologist Hans Spemann describedhow in another amphibian, the newt, a patch of mesodermsends out induction signals that tell adjacent regions of theembryo to form parts of the future animal, in particular neuraltissue. This "Spemann organizer," as it is called, won theembryologist a Nobel prize in 1935.
Another of Harland's post-docs, William Smith, identified thenot-yet-named noggin molecule, which he found expressed inthe Spemann organizer, as responsible for the crucial signalingthat induces neural tissue.
Since then, the mixed academic-industrial research group hasdiscovered noggin in the adult brains of mice and rats. What isan early embryonic tissue-inducer doing in the grown-upnervous system?
"I think it's a very good bet that it's serving a variety of roles,"said Regeneron's Yancopoulos. "The major reason we're excitedabout it is the fact that it's unrelated to any other growthfactors or neurotrophic factors. So we think this may be yetanother important player that's operating not only inembryonal neural development, but in the adult brain to keepit intact and doing well."
Regeneron and the UCB team have cloned and expressed thegenomic gene for human noggin, a protein 222 amino acids inlength. "Human and Xenopus noggin are very similar," Harlandtold BioWorld. "They have identical activity." Now, he said,they're hoping they can clone its receptor.
Harland laid out the three-step agenda of their currentexperimentation program with human recombinant nogginprotein, which he described as an atypical growth-factor-likeembryonic protein that acts as neural-tissue-inducing signal.
"One important step is to ask the question, 'Is noggin actuallyrequired for these induction processes?' " he said. "So far we'veshown it can mimic them if applied exogenously. So we'remaking a mutant in the mouse noggin gene in order to askwhether noggin is not only sufficient but actually required."
Together with Andrew McMahon at Harvard, Harland's team iscreating knock-out mice lacking the noggin gene to see howtheir nervous systems develop without it.
"Second, how does noggin do what it does?" Harland asked."What does it bind to? What kind of cellular response happens?
"Third, we're looking for other molecules that affect the type ofneural tissue that noggin induces." He noted that althoughnoggin induces brain-like tissue, this does not differentiate intoneurons.
Janet Rossant, who directs the developmental biology lab atToronto's Mt. Sinai Hospital, is one of several researchers whohave asked for some of Harland's noggin protein to study. "I'minterested in cellular development and early patterning inmouse embryos," she told BioWorld. "We have been able toachieve assays where we take ectoderm and recombine it withmesoderm and get neural induction in mice, the same way as inXenopus or chick embryos.
"What we'd like to know is whether noggin protein could takethe place of mesoderm in such assays," she said.
"The implications of Harland's paper in Science," Rossant added,"are far-reaching because there have been no real moleculesdefined at all before in any system of potential neuroinducers.This is really a 'first,' and it's very exciting."
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.