BOSTON -- Two biotechnology companies are taking aim atCharcot-Marie-Tooth (CMT) disease -- one with a test andanother with a possible treatment.

The Charcot-Marie-Tooth support group's medical advisoryboard announced last week at the 118th annual meeting of theAmerican Neurological Association here that it recommendedtrying Cephalon Inc.'s insulin-like growth factor-I (IGF-I) as atreatment for the peripheral neuropathy.

And in August, Genica Pharmaceuticals Corp. of Worcester,Mass., introduced a DNA test that diagnoses Charcot-Marie-Tooth disease type 1.

"Charcot-Marie-Tooth disease polyneuropathy syndrome is themost common inherited neuropathy, with a prevalence of atleast one in 2,500," said molecular geneticist James Lupski ofBaylor College of Medicine. He was instrumental in delineatingthe CMT gene abnormality in 1991.

Lupski's discovery came just 105 years after the disease wasdescribed simultaneously on both sides of the English Channel-- by neurologist Jean-Martin Charcot and his student PierreMarie in France and in London by neurologist Howard HenryTooth.

Unlike many other demyelinating neuropathies, notably ALS(amyotrophic lateral sclerosis) and muscular dystrophy, CMT isnot life-threatening.

"Most CMT patients have normal life spans," neurologist RobertLovelace of Columbia University's Neurological Institute andchairman of the medical advisory board of the Charcot-Marie-Tooth Association, told BioWorld. Karol Hitt, president andexecutive director of the CMT support group, based in Upland,Pa., estimated that 128,000 to 130,000 people in the U.S. havebeen diagnosed with CMT(perhaps as many more cases havegone unreported). Just 5,293 of these people are members ofthe association.

The disorder usually makes its frank appearance in latechildhood or the young-adult years. But an early sign of futureCMT is abnormally high arches so a child tends to walk on hisor her tiptoes. As the disease takes hold, foot and leg muscleslose strength, ankles sprain readily, hands and arms weakenand sensory signals fade.

Therapy usually takes the form of foot and hand braces orsurgery. While CMT is somewhat disabling, its sufferers rarelyneed to resort to a wheelchair.

Currently, IGF-I is undergoing clinical trials for ALS; a recentPhase I study concluded that the molecule, trademarked byCephalon (NASDAQ:CEPH) of West Chester, Pa., as Myotrophin, issafe and bioavailable. The ALS Foundation in San Francisco isnow enrolling 350 patients for a 10-center Phase II trial.

Cephalon's director of medical affairs, Elaine Alexander,attended last week's CMT medical advisory session, as didCeleste Chenet-Monte, product manager at Genica. Chenet-Monte told BioWorld that since the company put its diagnosticon the market some 10 weeks ago, Genica has sold just over400 CMT tests, priced at $395, and anticipates sales of $1million in 1994.

The pulsed-field gel electrophoresis assay recognizes thenucleotide duplication on human chromosome 17 that is thecause and hallmark of CMT type 1.

"Type 1 is where the myelin sheath of the nerve isprogressively deteriorated," Lovelace explained. In type 2, theaxonal version of the disease, "the internal axon, which carriesthe messages, is damaged, but not demyelinated." Both typescause similar symptoms.

Lovelace suggested that trials of IGF-I should begin with type 2CMT and eventually encompass type 1 as well. Alexander andChenet said they would consult their respective companies asto support for such a clinical study.

Chenet-Monte told BioWorld that Genica's CMT test requiresonly a peripheral blood sample, "obviating the need for moreinvasive assays currently employed, such as nerve conductionvelocity determination and calf muscle nerve biopsy."

The submicroscopic tandem DNA duplication on the short armof chromosome 17, which the test detects, represents about 1percent of the total chromosome's nucleotide length. Itsinheritance is an autosomal dominant trait that apparentlycauses CMT because it passes on a triple dose of the responsiblegene.

This PMP22 gene encodes a peripheral nerve myelin proteinwithin the duplication. Its overexpression by the triple genepresumably causes the CMT lesion.

Another gene on another chromosome, which also causes CMT,was reported earlier this month at the annual meeting of theAmerican Society of Human Genetics in New Orleans. In a last-minute addition to the conference agenda, neurologist KennethFischbeck of the CMT advisory board told the assembledgeneticists that he and his associates at the University ofPennsylvania have discovered an X-linked version of theneuropathy involving a mutation of the connexin 32 gene.

They found this DNA sequence more concentrated in peripheralnerve than in most other tissues, and located two pointmutations of the gene in five CMT families. These findings, asyet unpublished, Fischbeck told BioWorld, "are the firstnaturally occurring connexin mutations to be described."

-- David N. Leff Science Editor

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