Mutant mice born into the world with progressively weakeningmuscles are not a total loss. The "wobbler" mouse, as it's known toresearchers, mimics the symptoms of human motor neurondeficiencies, notably amyotrophic lateral sclerosis (ALS) _ LouGehrig's disease and spinal muscular atrophy.At the Cleveland Clinic, cages full of wobbler mice are about toembark on an eight-week preclinical study of two quite different nervegrowth factors to treat their hereditary motor neuron defectsimultaneously. They will receive combined doses of two recombinantproteins, ciliary neurotrophic factor (CNTF) and brain-derivedneurotrophic factor (BDNF).This extended synergistic regimen follows two just completed four-week courses of CNTF-plus-BDNF treatment, which were "found toarrest disease progression in wobbler mice for one month."Neurologist Hiroshi Mitsumoto, who heads the Cleveland Clinic'sneuromuscular disease section, reported this finding in the Aug. 19Science. Three of the paper's six co-authors are from RegeneronPharmaceuticals, Inc., of Tarrytown, N.Y.Mitsumoto told BioWorld Today that Regeneron is contributing$10,000 a year to the three-year co-treatment study, supplementing$120,000 from the ALS Association. In addition, Regeneron suppliedthe two recombinant nerve factors free, and collaborated closely withCleveland scientists in designing and reporting the study.CNTF Alone A Clinical Non-StarterTwo months ago, Regeneron unexpectedly terminated Phase III humantrials of CNTF alone, which it had conducted with Mitsumoto'sparticipation. (See BioWorld Today, June 24, p. 1.) He explains thatthe trial "had actually been completed, but it was decided to go nofurther, because it did not show any benefit."When announcing Regeneron's decision in June to "remove CNTFfrom the clinic," the company's corporate finance manager, SelenaChaisson, told BioWorld Today that it might in the future considercombined CNTF and BDNF for therapy.Mitsumoto noted that while his wobbler studies "may have somerelevance to human disease, safety and toxicity studies in animals mustcome first." He added, "One of these factors, at least, has to beapproved by FDA. A lot of things need to be done, and I am veryinterested to try in future."The spontaneously mutated wobbler, he recalled, was discovered some40 years ago in England. Born apparently normal, an afflicted mousesoon shows signs of advancing forelimb muscle weakness, followed byprogressive paralysis, atrophy, neurodegeneration and death.Both CNTF and BDNF promote the survival and differentiation ofdeveloping motor neurons, (the nerve cells that innervate skeletalmuscles), but by distinct pathways. Recent research has demonstratedtheir synergistic nerve-preserving effects in vitro. In the currentScience, 15 mice confirm it in vivo.Drug Synergy, But Not Placebo, SavedWobblers' NeuronsIn a blinded, placebo-controlled course of treatment, eight wobblers gotalternating subcutaneous injections of CNTF and BDNF; the otherseven, a dummy solution. One quantifiable measure of their responsewas paw grip strength, as gauged by dynamometer.After four weeks on both drugs, nearly half of the active-ingredienteight "attained a grip strength comparable to that of 10 unaffected littermates." Co-treatment "preserved the forelimb musculature, andattenuated muscle fiber atrophy."Meanwhile, the seven in the placebo cohort "rapidly and progressivelylost grip strength," and "paw-position abnormalities (digits curlinginward) progressed from mild to very severe," as their wobbleraffliction followed its normal downhill course of lethal motordysfunction.At Regeneron, none of the three co-authors of the Science paper wasavailable to speak with BioWorld Today, nor were any of thecompany's senior executives.In a Science editorial commenting on the Mitsumoto paper, cellbiologist Rae Nishi of Oregon Health Sciences University in Portland,wrote, "The dramatic effects of BDNF and CNTF on motor neurons inwobbler mice are important." Nishi added that "the characterization ofa double knockout mouse (that lacks both BDNF and CNTF) is all themore eagerly awaited."

-- David N. Leff Science Editor

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