Deb and Shawn Jenssen were used to frustration. Their kids had been turned away from studies. Doctors had questioned if they could really be showing signs of a disease even as it made it harder for them to walk.
All of it helped explain why that brief moment in an Orlando hotel conference room caught their attention — why it felt like hope.
The Jenssens were there for another conference on Duchenne muscular dystrophy. Back home in Madison, Ala., two of their triplets were displaying symptoms of the disease, one that was caused by a faulty gene and that progressively sapped muscle function. The kids weren’t quite 10 years old.
On stage was Doug Ingram, the CEO of Sarepta Therapeutics (SRPT), which was working on an experimental gene therapy for Duchenne. If the treatment worked, one dose could reshape and extend patients’ lives, which didn’t often last past 30. The company had run small trials of the therapy with narrow restrictions on who could participate, but for this next test, Ingram vowed, it wanted kids from a wider range of ages, with a wider array of Duchenne-causing mutations.
Maybe, the Jenssens thought, kids like their own.
“We’re trying to design a therapy that can benefit families across the globe,” Ingram told attendees at the Parent Project Muscular Dystrophy conference in June.
But then, as it always did, the other shoe dropped.
“We would love to develop life-changing therapies that could be transformative for 100% of children and young men who are living with Duchenne muscular dystrophy,” Ingram said.
There it was: men.
It made sense, based on the genetic underpinnings of the disease, that Duchenne was thought of as a boy’s disease. Most women who had the mutation, Deb included, appeared healthy, unaffected by it. If anything, the rare girl who showed symptoms didn’t have Duchenne; she was a “manifesting carrier” — something other than the boys whose photos filled advocacy campaigns and drug company websites.
Yet here were Megan and Sarah Jenssen, struggling to make the same protein that the boys couldn’t make, because of an error in the same gene that caused the disease in boys. One was showing moderate symptoms, the other more severe.
So during a question-and-answer session, Deb Jenssen stepped to the microphone. She introduced herself as a mother of two daughters with Duchenne.
“Mr. Ingram,” she said, “you talked about how you’re going to be starting this trial later this year that would be much more inclusive, and then at the end of your talk you made a very moving statement about making this available to 100% of patients with Duchenne. So my question is, first of all, have you thought about enrolling girls in this upcoming trial?”
She added, with a slight smile: “If not, can you think about it?”
Ingram seemed to take the question to heart and apologized for only referencing boys and young men. But, he explained, the focus needed to be proving that Sarepta’s therapy was effective, and that meant trials had to avoid any aberrant data that might distort the results. That meant boys only. He described the probability of including girls in the trial as “low.”
“I have literally not considered this particular issue before today,” he acknowledged.
The Jenssens appreciated that Ingram was not trying to spin them or give them false hope. The last thing they wanted was to somehow hinder the development of an effective therapy. But the moment spoke to the Jenssens’ fear of being forgotten from within their own disease community, where families cheered quests to find a cure for “our boys” and had long staged a big fundraising race called “Run for Our Sons.” Most clinicians didn’t know what to do with girls who looked like they had Duchenne. Some didn’t know such cases existed.
But with each day, the disease might be damaging the Jenssen girls’ muscles more extensively.
“If nobody knows about us,” Deb said later, “nobody’s going to help us.”
For generations, a Duchenne diagnosis was a final verdict. There were no meaningful treatments. But now multiple companies are developing gene therapies that, if they are shown to be effective, could help patients make a form of the protein they’re lacking, fundamentally altering their lives. For maybe the first time ever, there is genuine excitement in the Duchenne field.
Families of girls affected by the disease, however, fear the advances might pass them by.
Experts haven’t even settled on common language to describe these patients. Some said they had Duchenne, some said they had “Duchenne-like phenotypes,” and others said they were manifesting carriers with varying degrees of symptoms. Some patients were told they had Becker muscular dystrophy, a less severe version of Duchenne.
One in 5,000 boys is estimated to have Duchenne, and each generally follows a similar pattern of progression. But among girls who carry the mutation, only a fraction will have serious limitations, said Dr. Jerry Mendell of Nationwide Children’s Hospital in Columbus, Ohio. He estimated that fewer than 5% of female carriers might one day lose their ability to walk, and often at later ages than boys, who start using wheelchairs around age 12.
It all put families like the Jenssens in an awkward spot. They understood why there was so much attention on boys, given the numbers and the certainty of their prognoses. They did not want to minimize the tragedy of their cases.
But for girls, cases of serious manifesting carriers are so sporadic, so variable, and so poorly studied that no one could tell them if they will lose function, or follow the same trajectory as boys, or how quickly. The uncertainty was formidable.
What Shawn and Deb, 43 and 42, did know was what was going on with their girls right now.
Anna, the sassy redhead, didn’t carry the Duchenne mutation. She was the youngest yet tallest of the triplets, and seemed older than her years.
Megan, who had meticulous handwriting and French-braided Julie the American Girl doll’s hair, had symptoms that were tame compared to boys her age. But she had never been able to climb a jungle gym. She loved to dance, but gave up classes because she couldn’t keep up.
Sarah, who was so sweet and always smiling, seemed to be teetering toward a decline. She was having more trouble with stairs and could no longer ride her adaptive tricycle.
For Sarah and Megan, there were challenges inherent in having a condition that diverged from the norm of a disease — what doctors thought it should look like, who should have it, who was most likely to benefit from a clinical trial.
A few years ago, the Jenssens started making the drive up to Columbus so Sarah and Megan could see Mendell, one of the country’s top Duchenne experts, who helped invent Sarepta’s gene therapy and has run the clinical trials. They’re now going for twice-a-year visits.
Mendell said some of the manifesting carriers he treats have conditions “that absolutely simulate or duplicate what boys have” and that are even more advanced than the cases of the Jenssen girls.
It was obviously difficult to see boys with Duchenne, Mendell said. But there was something “almost unfair” for girls who face the consequences of this disease.
“Most escape that, except for the girls who end up manifesting,” he said. “And I don’t know whether we can really do anything at this point.”
Deb grew up in the Chicago area and joined the Air Force after high school. She met Shawn while they were both stationed at Vandenberg Air Force Base in California.
For much of her life, Deb had presumed marriage and kids weren’t in her future. Her older brother Michael — her best friend, really — had had Duchenne. He was diagnosed at 8, got crutches at 11, and was in a wheelchair at 12. He always kept his sense of humor, and his Catholic faith deepened as his disease progressed. He died in 2003, at 28. Deb also had a cousin die from Duchenne.
She knew she carried the mutation as well, and that any son she had would have a 50% chance of having Duchenne.
The mutation, in a gene called DMD, disrupts the production of dystrophin, a rope-like protein that protects muscles as they work. Deb and Michael had each inherited from their mother a faulty copy of the gene, which resides on the X chromosome. But Deb had a second, healthy copy of the gene on her other X chromosome, which could make enough dystrophin to compensate, to keep her muscles from wearing down. Men only have one X chromosome, so Michael had no backup. (Other conditions inherited in this way include some types of hemophilia and a form of color blindness.)
A few years after Deb and Shawn got married, their desire for kids grew. They had moved to the Huntsville area, where they both work in the aerospace industry. And they found a way to have children that they believed would expunge the Duchenne mutation from their family line.
They created embryos through IVF, which then went through preimplantation genetic diagnosis — a way to peer into the DNA of embryos to make sure they had the right number of chromosomes and no disease-causing mutations. They wanted to make sure they only tried starting a pregnancy with healthy embryos.
Two of theirs were viable, it turned out, and both were girls — a relief. One had the Duchenne mutation. Still, the doctor recommended they transfer both to Deb’s womb, in case one didn’t implant successfully. Yes, it would mean that the Jenssens were preserving this mutation, but, the doctor told them, this daughter would be like Deb — a carrier, but healthy, not affected by it.
They moved forward with both embryos. One of them split, creating identical twins in a set of triplets. Twenty-nine and a half weeks later, Sarah, Megan, and Anna arrived.
Within months, it became apparent something was not quite right.
Sarah and Megan were late to sit up and then stand. A local doctor attributed the delay to the fact that they were born 10 weeks early. But that never made sense to the Jenssens: Why were Megan and Sarah missing milestones when Anna was reaching them, sometimes a year ahead of her sisters?
When Sarah finally stood up one day, it slid into focus. She stuck her legs out wide and hitched herself up by crawling her hands up her legs. That’s not a developmental delay, Deb thought when she saw it. That’s Gower’s maneuver — a sign of Duchenne.
Deb and Shawn began researching Duchenne cases in girls and told the local doctor about it, but it took another year before they were referred to specialists down in Birmingham. The doctors there suggested for another year that it had to be some developmental issue. The Jenssens were split between their sense that it was probably Duchenne and their wishes that it wasn’t.
“I was always hoping we were wrong,” Shawn recalled.
Finally, when the girls were 4, the doctors did a genetic test on the girls. It showed they were carriers, like their mom. But then they took a muscle biopsy from Sarah. When they looked at a slide of it, what was most notable was what was there in inadequate amounts: dystrophin. These were Duchenne symptoms.
Megan and Sarah were the victims of bad luck.
In each cell with two copies of a gene, a cellular railroad switch turns one on and leaves one off. In roughly half of their cell nuclei, then, female carriers of Duchenne would be expected to express the normal gene, producing enough dystrophin to defend their muscles against wear and tear.
Sometimes though, by random chance, a majority of cell nuclei will activate the copy of the gene with the Duchenne mutation, leaving fewer nuclei pumping out dystrophin. The less dystrophin, the more severe the signs of the disease.
This was what the Jenssens had just been told was happening with Sarah and Megan.
After they learned the news, on their way back home from Birmingham, the Jenssens made a pit stop at Chick-fil-A. Deb looked at their girls, who were so happy with their ice cream, and tried to hold it together. They had tried so hard to protect their kids from Duchenne, and now they had two facing it.
“If nobody knows about us, nobody’s going to help us.”
After the diagnosis, and without other treatments available, Deb started scanning through clinical trial postings. The criteria for enrollment would specify “male, older than 5 years old,” or “ambulatory boys.” She would reach out and ask about girls.
Sometimes she was told no, sometimes she didn’t get a response, sometimes she was told girls couldn’t have Duchenne.
Drug companies “don’t think about it because, 99% of the time, it’s a male disease,” said Pat Furlong, the CEO of Parent Project Muscular Dystrophy, whose two sons died from Duchenne. “Until you see one of these little girls, I think it doesn’t dawn on them that some manifesting carriers really look like they have Duchenne.”
Experts said there are valid reasons not to include girls in clinical trials.
Some studies measure dystrophin production to test whether a therapy is working. Boys with the disease often don’t make any dystrophin, giving researchers an easy baseline with which to judge whether a treatment is effective. Manifesting carriers have such variability in their dystrophin levels that it would be difficult to gauge improvements.
The most rigorous clinical trials also include participants who receive placebos — a control group. But the disease affects girls in such differing ways that it would be hard to find matching girls for a control group.
Without access to treatments, the Jenssens have been accompanied by both omnipresent hope and anxiety. They hoped progression of the girls’ disease would follow such a slow arc that they could hold out for a cure. They prayed something would arrive while the girls could walk. They know this might all be different for girls, but that no one can really tell them how.
The Jenssens have been upfront with their daughters about their disease, as best as they can be. The girls know that their uncle and Deb’s cousin died from it. But when they ask if they will wind up in wheelchairs, all their parents can say is that they’re not sure.
When the girls sleep, they strap braces on their legs — pink for Megan, teal for Sarah — to stretch out their ankles. The tighter their muscles, the more trouble they might have walking. They have always struggled running, so during recess, they sometimes sit by themselves while the other kids play.
Even the shape of their bodies exhibits the disease. To keep their balance and calibrate for their weakened muscles, they arch their backs and stick out their stomachs. It’s called lordosis, but more simply: If Megan and Sarah stood back to back, their upper bodies would look like parentheses.
“If you think our hands are full, you should see our hearts,” says a sign on a shelf in the Jenssens’ house.
There are hints that the Duchenne community is inching toward thinking more about girls. The “Run for Our Sons” is now the “Race to End Duchenne,” in part because of manifesting carriers. This year’s Duchenne conference featured a special session dedicated to manifesting carriers.
Some scientists are paying more attention, too.
Nationwide Children’s launched a study to examine the health effects of the Duchenne mutation in women. Researchers had known that carriers — even those who didn’t show other symptoms — were at risk for cardiac problems. But far more carriers in the study — Deb included — showed signs of heart damage than had been anticipated.
The day after Deb questioned Ingram, the Sarepta CEO, at this year’s conference, he reiterated to them that he would keep thinking about girls and trials. The company’s patient liaisons have been in touch since then.
At the conference, the Jenssens also met Dr. Stanley Nelson, from UCLA’s Center for Duchenne Muscular Dystrophy. He is now trying to get the girls a drug called ataluren through an expanded access program, which provides an avenue for patients not in trials to obtain experimental medications.
Sarah and Megan have what is called a nonsense mutation in their DMD gene. The mutation sends a premature stop signal as dystrophin is manufactured, rendering the portion that has been made inoperable. Ataluren, which is made by PTC Therapeutics (PTCT) and which is approved in Europe for Duchenne, was designed to treat patients with these types of mutations.
(The Jenssens have not tried to get a different Sarepta therapy called Exondys 51, which was approved in 2016, because it works on another type of mutation. Last week, the Food and Drug Administration rejected a separate Sarepta drug that also targeted a different DNA sequence.)
“It’s a harsh disease because it’s progressive,” Nelson said. “There are reminders that it’s progressive every day for every parent and for every clinician with every visit.”
Nelson knows this well. His son, who is in high school, has Duchenne and has been in a wheelchair since he was 13.
“It’s quite frustrating. There’s a feeling that there are winners and losers, and there’s a feeling that your child’s mutation is being worked on or your child’s mutation is not being worked on.”
Other concerns loom for the Jenssens. They dream of a gene therapy getting approved, but worry they still might not get access to it. Any such therapy would likely have a list price in the millions, and already, insurance companies are clashing with families over who is eligible for approved gene therapies and who is not.
It was the fear of being “boxed out,” as Shawn put it.
For now, though, they were enjoying a summer Sunday in their backyard. It was the day before the girls’ 10th birthdays. A few days later, they would be starting fourth grade, having to ride the elevator instead of taking the stairs, sitting on chairs instead of the ground when their class sat in a circle, and occasionally being the butt of another kid’s joke about how they ran slowly or couldn’t go up steps.
Deb sometimes thinks back to the moment when they were trying to get pregnant and the doctor pushed them to transfer the second embryo. In a way, it led to something they had tried to avoid.
“But then I go back to my daily life,” she said, thinking about having three daughters and not only one. “And these kids are the best thing that ever happened to me, and they’re so happy and so sweet, and I’ve learned so much from being their mom. This actually is a pretty great life having these kids.”
Sarah was sitting on a hammock-like swing and wanted to get off. At first, she insisted she didn’t need any help. She planted her left arm and pushed off it. She leaned forward and stuck out the tip of her tongue, like an athlete in the zone. But her bottom wouldn’t budge.
“Can I help you?” Deb asked.
“Yes,” Sarah said. “Come help me.”