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Finding hope in a spider's bite

Venom holds a key to possible therapy for cruel illness

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By Henry L. Davis
News Medical Reporter
November 7, 2010

Duchenne muscular dystrophy is a cruel disease.

By age 10, affected children, almost always boys, usually need braces to walk.

By their teen years, most depend on a wheelchair.

And as they grow into manhood, they lose their ability to breathe. Few survive beyond their 30s.

There is no cure, and the standard treatment of steroids can slow -- but not stop -- the progressive muscle weakness, forcing families into a race against time.

All of which is why Jeffrey Harvey, a Clarence stockbroker, couldn't sit still when his grandson, also named Jeffrey, was diagnosed with the disease more than a year ago.

Harvey began to look for potential new treatments, surfing the Internet for anything with promise. Out of curiosity, he searched in his hometown, which led him to a laboratory at the University at Buffalo and to a tarantula spider named Rosie.

The story of his search highlights a novel potential treatment for muscular dystrophy -- one of several therapies on the horizon. It also shows how challenging it can be to bring a drug from the laboratory to a patient's bedside.

"There is just no drug for these kids other than the steroids to strengthen the muscles, and the steroids have serious side effects," said Harvey, whose grandson is now 3.

UB biophysicists had found a protein in tarantula venom that showed promise against muscular dystrophy, but the idea was greeted skeptically. No one responded when they shopped it around to pharmaceutical companies earlier in the decade.

Then Harvey called.

"I didn't know what to make of it at first," said Frederick Sachs, whose laboratory discovered the protein known as GsMTx4 and is a world leader in researching how cells respond mechanically to changes in their environment.

A few months after meeting, Harvey, Sachs and two colleagues, Thomas Suchyna and Philip Gottlieb, launched a small biotech company with hopes of doing what the big drug companies wouldn't do.

"I want my grandson to be able to have this drug," Harvey said.

Muscular dystrophy -- the disease whose treatment is championed by comedian Jerry Lewis -- is a group of nine inherited conditions that cause wasting away of muscle. Duchenne muscular dystrophy, named after the French physician credited with its discovery, is the most common childhood form and the most severe.

The gene that causes Duchenne muscular dystrophy instructs the body how to make a substance called dystrophin, a protein that helps muscle cells keep their shape as they stretch and contract. In boys with errors in the gene, the instructions get scrambled.

The disorder affects 1 in 3,500 males, with an estimated 18,000 cases in the United States.

Much of the research on new treatments is focused on stem cell therapy that can repair damaged muscle or gene therapy that can repair a defective gene or block its bad instructions.

Sachs' group takes a different approach.

The body's cells depend on channels in their membranes that open and close like valves. These gateways allow important substances, including calcium, sodium and potassium, to enter or leave the cells. If the channels don't work properly, people get sick or die.

Sachs' laboratory in 1984 discovered a group of these channels in muscle cells that respond to mechanical stress, such as being stretched by the contraction of a muscle. The researchers figured that if they could find a chemical that activated or shut off the channels, that chemical might serve as a drug to treat disorders that arise from stress-sensitive channels that open too much or too little.

They didn't have access to a vast collection of chemicals that pharmaceutical companies keep on hand. So they tested venoms, starting with those from arachnids -- the scientific name of a class of animals that includes spiders and scorpions.

Venoms contain hundreds of compounds, the function of most of which is unknown. Tarantula venom, which is obtained by anesthetizing and milking the creatures, provided the researchers with their "aha!" moment, but led to much more work. They had to find out which of the hundreds of compounds produced the effect.

The lack of dystrophin in boys with muscular dystrophy causes an influx of calcium into muscle cells leading to atrophy. GsMTx4, which the researchers learned to synthesize, couldn't repair the source of the problem, but could slow the rate of degeneration.

"Pharmaceutical companies weren't interested, probably because the idea that this protein we found affected a mechanical problem in cells seemed foreign to them," Sachs said.

The new company, Rose Pharmaceuticals, is named after Rose, Sachs' grandmother, and Rosie, his pet Chilean Rose tarantula. Tarantulas may look scary but their venom is relatively harmless to humans.

In collaboration with the Wellstone Muscular Dystrophy Center in Washington, D.C., the team tested GsMTx4 on mice with muscular dystrophy. The substance increased muscle strength and caused no deaths, sickness or side effects.

Sachs sees GsMTx4 as potentially one element in a cocktail of drugs that Duchenne muscular dystrophy patients will likely take as more therapies come on the market.

"You'll probably need a mix of drugs to repair cells, but it's better than nothing," he said. "I'd love to see a kid get out of a wheelchair before I die."

This summer, the Children's Guild Foundation awarded Sachs' group $125,000 to improve the therapy, and the UB Center for Advanced Biomedical and Bioengineering Technology awarded $80,000.

In September, the Food and Drug Administration gave GsMTx4 orphan drug status, a designation for experimental treatments of rare conditions that helps speed development.

Now, comes the difficult part -- seeking an estimated $3 million to fund testing before the drug goes into trials in children.

"The thing is, unlike a lot of others, we already have the drug. If we had the money to get it through preclinical testing, we might have it on the market in three years," Harvey said.

That's not much money or time in the world of drug development, where companies typically spend hundreds of millions of dollars and more than a decade on one product. Still, it's frustrating with the short life expectancy of children with Duchenne muscular dystrophy.

"These kids usually only live into their mid-20s," Harvey said.

One possible source of help may be the Parent Project Muscular Dystrophy, the largest nonprofit organization in the United States focused on Duchenne muscular dystrophy.

"The tarantula venom is definitely a different approach, and we're interested in it," said Sharon Hesterlee, the organization's senior director of research and advocacy.

Early next year, a consortium of dozens of institutions across Europe and elsewhere that came together to improve treatment of neuromuscular diseases will review Sachs' therapy. Based on its conclusions, Parent Project will put money into the endeavor.

For patients like Raymond Holcomb Jr. of Tonawanda, the slow progress toward new treatments, let alone a cure, can be a source of frustration. The promise of medical advances, whether from venom or elsewhere, hangs tantalizingly just out of reach.

"I'm 39 years old and realize my clock is ticking," he said. "But if I'm not hopeful, life would be unbearable."