Kara Jacobs of Eudora, Kan., knows better than most parents what it’s like to live every day between hope and reality.
The reality is that Zane, 7 and youngest of her three boys, was diagnosed two years ago with Duchenne muscular dystrophy.
“Zane!” Jacobs, 29, called recently as she stood in her backyard. She watched with a half smile, knowing he wouldn’t listen as he and brothers Aidan, 10, and Taegan, 9, drenched their new sneakers while ambling about in the creek behind their home. “Get out of there.”
Duchenne is a genetic neuromuscular disorder that is linked to an X chromosome mutation and affects boys. It robs them of the vital protein called dystrophin, wastes muscles and puts boys in wheelchairs, typically by age 13, until it eventually affects their hearts.
The reality is that although this is a good day for Zane — he’s not stumbling or falling as if his ankles have turned to gel — his dad, 1st Sgt. Josh Jacobs, a U.S. Army recruiter, will continue to say the same prayer on this night as he’s said every other night.
“I pray to switch places,” said Josh Jacobs, 32. “Give him my life. I’ll take his disease.”
The hope is that perhaps the two white corticosteroid tablets Zane now takes each day, part of an experimental trial out of the University of Kansas Medical Center, might in some small way be slowing the disorder’s progression.
The Jacobses don’t know which of two steroids Zane is on. They don’t know the dose. They don’t even know if he’s on any steroid at all at some points in the study, or is receiving a placebo. They watch his body and moods for signals.
“On one hand, I’m just making my son a guinea pig,” Kara Jacobs said, “but on the other hand, this could possibly work. Even if it will not work for Zane, maybe it will point them in the right direction for another child.”
What the Jacobses do know is that they are grateful to live some 40 miles from the KU Medical Center in Kansas City, Kan. The medical center in the past decade has emerged as a leading research center in the United States for investigation of Duchenne and a host of other neuromuscular diseases.
While some are little-known and possess difficult-to-pronounce names like facioscapulohumeral muscular dystrophy, others such as amyotrophic lateral sclerosis, also called ALS and Lou Gehrig’s disease, are far more familiar.
At KU, a serious effort to grow its research in the field began 15 years ago.
In 2001, the KU Medical Center conducted no neuromuscular research and the adjacent University of Kansas Hospital, which treats patients, had no physicians dedicated full time to treating neuromuscular diseases.
Now, the medical center reports, it is leading or is part of some 60 clinical scientific trials, with 10 finishing up, 40 ongoing and another 10 about to start, many of which test new or existing therapies.
On the clinical side, the hospital’s neurology department has six full-time physicians treating such cases, plus nine full-time staff members and other faculty running studies out of the KU Clinical Research Center in Fairway.
National Institutes of Health funding for the neurology department stands at $6.5 million a year, up from zero in 2001. Other funding — from pharmaceutical companies, the Muscular Dystrophy Association and other groups — has risen in that time from $1.1 million to $3.5 million.
The prime reason is the hiring of Richard J. Barohn originally of St. Louis, 59, and a 1980 graduate of the six-year medical program at the University of Missouri-Kansas City. He became a leading neurologist for investigating and treating neuromuscular diseases at the University of Texas Southwestern Medical Center in Dallas. KU hired him away in 2001.
“I helped train Rick Barohn,” said muscular dystrophy researcher Jerry R. Mendell, director of neurosciences and director of the Center for Gene Therapy at the Nationwide Children’s Hospital in Columbus, Ohio. “He has been very successful. He’s done a very good job at putting together clinical trials.”
Pulling in patients
Each week, patients from across the region arrive at KU Clinical Research Center, although in one instance they came from around the globe.
That drug trial involved Pompe disease, also a rare genetic disorder that progressively weakens muscles.
The cause of Pompe is a genetic mutation that prevents the body from producing a crucial enzyme that rids muscle cells of stored sugar. It affects males and females.
If the disorder appears in infancy, those infants often die before their first birthdays because of the effect on heart and respiratory muscles. The disease tends to be less severe when it appears in adulthood, but it also progresses with age, weakening the body’s trunk and limbs. Adults, too, may end up on a ventilator.
Pompe is rare enough — arising in about 1 in 40,000 people — that when KU in 2012 began testing an experimental drug intended to replace some of the missing enzyme, three adult patients flew in from New Zealand to be part of a 24-week trial. The patients stayed in Kansas City hotels for eight weeks to be infused with the drug every other week and, afterward, flew back to finish the trial in Australia.
“We are connected with 60 other research institutions around the country and others around the world,” Barohn said. “You can’t do it alone. We have become a real leader in running these large, multicenter neuromuscular studies.”
Recently, Carolyn Ester, 68, of Kechi, Kan., north of Wichita, drove to Fairway with her husband as she’s been doing each month for more than a year. Ester is part of a two-year trial of a drug that she hopes might alleviate symptoms of her disorder, inclusion-body myositis, given the familiar initials IBM.
“I found out how far spaghetti can fly in my house,” Ester joked about her now-unsure muscles. “It went from the refrigerator into the living room. It took two hours to clean that up.”
“Myositis” refers to inflammation of the muscles, caused by anything from infections to medicines to injuries to acquired or inherited diseases.
The Myositis Association describes four major types, including inclusion-body myositis.
Dermatomyositis is easy to recognize because it causes skin rashes. It includes a sub-type connected to cancer.
Polymyositis affects women more than men. Its hallmark is gradual muscle weakness beginning close to the body’s core, at the neck, hip, back and shoulders, but also can cause lung tissue to inflame.
Juvenile myositis affects children, causing rashes and often affecting stomach, upper arm and leg muscles.
It’s unclear what causes Ester’s inclusion-body myositis. Typically, the condition affects men more than women and is unusual to crop up in people younger than 50. Ester, who retired from nursing after 40 years, saw the first signs in 2005.
“It was crazy,” she said. “One day at work I was going to get lunch. I tripped and fell flat on my face. I had just bought some new Crocs. I blamed it on my shoes.”
As years passed, her legs turned leaden. Climbing stairs or rising from a chair became arduous.
In 2010, she received the diagnosis. Some people will end up having troubles swallowing. Ester said she, too, has to be careful she doesn’t choke on steak or ice. She walks moderately well, but many people with IBM do end up using electric scooters.
“The thing about this disease is that no two people are exactly alike,” said Ester, who also plays piano and organ. “If I get to the point where I can’t play the piano, it will really bug me.”
The trial she’s now part of could be helping, but it’s unclear.
“I said, ‘Look, if someone doesn’t do this,’” Ester said, “‘we won’t find a cure for this crap.’”
She’s part of a trial of a drug called bimagrumab, a monoclonal antibody developed by Novartis Pharmaceuticals that might help reduce muscle swelling and increase mobility. She doesn’t know what dose she’s on, or even if she is on the placebo, although she guesses she’s not.
“I’ve noticed a little more strength,” she said.
New therapies emerge
Because of research, the futures of some children with Duchenne are more promising than ever.
No cure for the disease yet exists, researchers emphasize.
But, said Mendell of the Nationwide Children’s Hospital, “I can tell them we can dramatically change the natural history of the disease.”
In the 1960s, the average age of death of boys with Duchenne was 14. Better orthopedic care, nutrition, ventilation support and early use of steroids have helped prolong life and health.
“Now the average age is 25,” said Grace Pavlath, a researcher in pharmacology at Emory University School of Medicine and senior vice president and scientific program director for the national Muscular Dystrophy Association. “You have people who live into their 30s and even 40s.”
A current and promising area of research, she said, involves the development of new drugs, including ones that try to replace the vital dystrophin protein, while others work on cells to allow them to produce more energy to keep muscle cells alive longer.
Especially exciting to researchers are advances over the past five years on “exon-skipping” therapies.
Exons are segments of genes that contain the instructions for creating a protein. Pavlath said that one can think of an exon in genes just as one might think of the individual letters that make up a sentence such as “the cat jumped over the fox.” Take out letters, add extra letters or toss in nonsense symbols, and the sentence becomes garbled or unreadable. It doesn’t work.
The same applies to Duchenne muscular dystrophy. In healthy individuals, the gene that codes for dystrophin contains 79 exons. But in Duchenne, the disease is mostly caused by a mutation in which some of the exons are deleted or duplicated.
When the cell’s machinery runs along the DNA in an attempt to “read” the gene to produce a complete dystrophin protein, it runs into the missing or duplicated exon. The machinery derails. No functional dystrophin protein is produced.
But “exon-skipping” medications allow the cell’s machinery to skip over certain bad or missing exons to produce a dystrophin protein which, although it has a tiny chunk missing, is more functional, Pavlath explained. The hoped-for result is a form of Duchenne’s that has been slowed down and made milder, giving boys greater and longer mobility and offering them longer lives.
Over much of the past decade, two major players, Sarepta Therapeutics, based in Cambridge, Mass., and Prosensa, a Dutch company in cooperation with GlaxoSmithKline, had been testing their own versions of exon-skipping drugs in clinical trials.
The Sarepta drug is called eteplirsen. The other drug, which has since been acquired by BioMarin Pharmaceuticals in San Rafael, Calif., is called drisapersen. Both focus on skipping a particular segment, exon 51, a mutation that accounts for about 13 percent of boys with Duchenne.
In clinical trials, including those at KU Medical Center, boys on the drugs have shown to do somewhat better, walking longer and more ably when asked to conduct a hallmark test for the disorder called the 6-minute walk test.
“I would say that we are at a key turning point with some of these diseases, including Duchenne,” Barohn said.
In August, meanwhile, a somewhat similar Duchenne drug called ataluren — produced under the brand name Translarna by New Jersey-based PTC Therapeutics — received conditional approval by the European Union, making it available through physicians in 31 European countries.
Instead of an exon-skipping drug, it is a “stop codon” drug. In some versions of Duchenne, a mutation puts a stop in a gene’s production of the protein, like putting a period in the middle of a sentence, or a wall in the middle of a road. The new drug allows the machinery to move past the obstacle to produce a form of dystrophin.
“Ten years ago you wouldn’t have seen any of this,” said Pavlath, the Muscular Dystrophy Association vice president. “It is tremendously exciting.”
‘I am hopeful’
Kara and Josh Jacobs hope that their son will be right for a future trial. Her boys are getting older, she said, and have started asking questions.
“The other two, they know that eventually he won’t be able to walk,” Kara Jacobs said.
Zane’s muscular dystrophy, unfortunately, is caused by a different set of mutations rather than exon 51.
Both BioMarin and Sarepta have other Duchenne exon-skipping drugs in development for exons 8, 44, 45, 50, 52, 53 and 55. But they are in early stages.
Aidan, the oldest brother, has questioned his mom about whether there is a medicine for Zane, and also has asked graver questions.
“It’s one of those things,” Kara Jacobs said. “You don’t want to lie to your kids. You also don’t want them to obsess about it.”
About Zane: “He knows that his legs are different. He knows his legs tire easily. He understands that he will one day have a wheelchair.”
At home, he climbed on his electric scooter, laughing. Taegan, kneeling on his skateboard, clung to the rear of the scooter while Aidan, kneeling on his own skateboard, clung to Taegan.
“I pray and I hope and I dream that my son will be a 30-year-old Duchenne boy, that he will be able to get married, that he will have children,” Kara Jacobs said. “Yes, I am hopeful. Yes, I pray for it. Right now, I stay in the now.”