COLD SPRING HARBOR, N.Y. -- Disappointment and optimismmark the attempts to treat Duchenne muscular dystrophy (MD)by gene replacement. Molecular geneticist Ronald G. Worton ofToronto's Hospital for Sick Children reported those effortslate last month to a Gene Therapy meeting here at the ColdSpring Harbor Laboratory.

Duchenne MD is a muscle-wasting, crippling disorder thatbegins in early childhood, puts most of its victims inwheelchairs before adolescence and leads to death by age 20.Its cause is total lack of dystrophin, a large moleculeessential to the integrity of muscle fibers.

The sex-linked, recessive genetic disease afflicts only boysbecause the gene defect is on the X-chromosome; their mothersare carriers. DMD strikes one in 3,500 live male births, saidneuroscientist George Karpati of McGill University'sNeurological Institute in Montreal, whose team conducted theclinical trial reported by Worton.

"It is a very common genetic disease," Karpati told BioWorld,"probably second in frequency to cystic fibrosis."

An average of 1,100 new cases occur each year in the U.S.,about one-third of them caused by new gene mutations.

After Worton and two other researchers independentlydiscovered the dystrophin gene in 1986, animal experimentsbegan to inject myoblasts (precursor cells to muscle fibers)into the muscles of mice. Encouraged by the results, a numberof centers in the U.S. and Canada have designed clinical trialsto culture myoblasts from donor relatives and injected themyoblasts into the weakened muscles of patients.

In Montreal, Worton said, eight DMD boys 6 to 9 years oldreceived 55 million myoblast cells, cultured from musclefragments donated by their fathers, through 55 needle sites onone upper-arm bicep. In the other arm the received 55injections of saline as a placebo control. The Phase I trial,both by measurement of muscle strength and polymerase chainreaction (PCR) analysis of messenger RNA from the donordystrophin gene, failed to create a significant number ofhealthy new muscle fibers. The trial ended last spring,

"So it's back to the mouse-model drawing board," said Karpati,to improve the myoblast culture and delivery procedures. Buthe said that the latest animal results are "extremelyencouraging" and he predicts that "in a couple of years, thismode of myoblast transfer treatment might be ready forclinical trials."

"If these don't pan out, we will try to develop gene therapies tointroduce functioning dystrophin genes, either in a plasmid ora viral vector.

The American Muscular Dystrophy Association (MDA) in Tucson,Ariz., has been a main source of funding for Worton's andKarpati's work. Now, said Donald S. Wood, a scientific adviserto the organization, MDA is developing specific plans to stepup its support for gene therapy.

"We must accelerate efforts to overcome technical challengesto the largest human disease-causing gene ever discovered," hetold BioWorld. "At 2,500 kilobases, it's too big to stuff into anexpression vector, so we're putting our money on minigenes."

-- David N. Leff Science Editor

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