McKINNEY, Texas (AP) — Ever since doctors diagnosed his son with a rare disease, Doug Woleben has spent every evening on his computer, searching for a way to save the 6-year-old's life.
He has mastered the foreign language of medical literature, corresponded with drug companies, flown his family long distances for experimental treatments and emailed academic researchers who might know of something, anything, that could help his son.
Some days have brought hope, but many more have brought frustration.
There was the time Doug, an engineer for a telecommunications company, read about a promising experimental drug and asked its manufacturer to let Will, his son, into its clinical trial. The company said to check back in a few months. That was in 2014.
Then Doug and his wife, Kasey, who live in McKinney, enrolled Will in a trial in Houston, and drove him back and forth for tests. To Doug and Kasey's delight, the drug compound seemed to help. Will's condition stabilized, and he seemed to grow stronger. But then the company pulled its drug and canceled the trial. There wasn't enough data to show that it worked, executives told them.
"We were dumbfounded," Doug told The Dallas Morning News .
"This is all we have," Kasey told the executives in a conference call. "Let's keep him on this until we find something else."
Just as the Wolebens were running low on options, their neurologist at UT Southwestern Medical Center sent Will's case file to a new colleague named Steven Gray.
Gray, a scientist who joined the faculty in December, has made it his mission to develop treatments for fatal childhood diseases like Will's. Not only would this approach, known as custom gene therapy, target Will's symptoms, it might fix their underlying cause: a single defective gene out of Will's more than 20,000.
There was one hurdle to launching the experiments that could pave the way to a treatment: The Wolebens would have to raise $300,000.
The rarest of the rare
After two decades of promise and setbacks, gene therapy is going through a renaissance. Last year, the government approved the first technique that transfers healthy genes into patients with defective ones. Such transfers have preserved patients' sight and shown promise in treating kids with muscular dystrophy. Scientists are already working on ways to inject healthy genes into the womb, to stop inherited diseases before they do damage.
These advances have brought the Wolebens hope where they previously had none.
But Will's illness is not just rare — it's ultra rare. Only a few thousand people around the world live with his particular genetic mutation.
For that reason, drug companies have little incentive to invest in a cure. And federal and foundation grants are hard to come by, not only because diseases like Will's affect so few people, but because there is too little data about them to determine which course of study might be the best. Meanwhile, government funding has failed to keep pace with the rising number of grant applications, forcing many researchers to look elsewhere for support.
"It's the most unfair thing in the world," said Gray. "If the parents don't become advocates, and if they don't become funders, then it's just not gonna happen."
The Wolebens find themselves at a crossroads. A medical breakthrough has lifted their chances of saving Will, yet society hasn't solved the problem of how to pay for those treatments.
So the Wolebens and every other family Gray has worked with have had to do the unfathomable: care for gravely sick children while raising hundreds of thousands of dollars. They do this knowing that a treatment may never materialize, or that it could come too late for their sons and daughters. And they do it amid difficult questions about the role patients should play in prioritizing — and funding — disease research.
'Our lives were shattered'
Long before doctors put a name to Will's condition, Kasey worried about her son.
Will was born healthy and grew into a cheerful, active toddler who loved to dress up as a fire chief and run around the house putting out imaginary flames with his toy fire extinguisher.
As he neared his second birthday, Will's growth slowed and he began to stumble and fall. Soon, his parents noticed what they called "resting episodes." Will would suddenly collapse on the floor while running and playing. He'd be awake and alert but unable to move.
These episodes happened more and more frequently, so Doug and Kasey alerted Will's doctors, who sent them to an array of experts. A gastroenterologist ruled out digestive problems. An endocrinologist ruled out thyroid and hormone disorders. A neurologist ruled out seizures.
"They said, 'He's fine. He's talking, walking, eating. There's nothing wrong with him,'" said Kasey.
But she and Doug continued to fret. In April 2014, Kasey was sitting on her living room sofa nursing Will's younger sister, Lauren. Will, then 2, came running over to grab a handful of blueberries from the coffee table and fell down. "I'm OK, Mom," he said from the floor. "I just can't get up right now."
Kasey looked over at her son, lying on the rug by the table. He kept assuring her that he was fine, but the look on his face showed fear and worry. She could tell he knew something wasn't right and that it scared him.
She called Doug, who was at work, and asked him to come home and stay with Lauren. She took Will to the emergency room.
In the ER at Children's Medical Center Plano, doctors performed a CT scan and noticed dark spots on Will's brain. They told Kasey it looked like he'd had a stroke, but they needed a closer look. They sent Will by ambulance to Children's Medical Center Dallas, which is staffed by UT Southwestern physicians. Doctors there admitted him to the hospital while they performed more tests, including an MRI scan.
A few days later, a team of doctors walked into Will's hospital room and asked Kasey and Doug to follow them down the hall. Together, they entered a smaller room where still more doctors sat around a conference table. Kasey noticed that a slide presentation had been set up on a screen. She felt a sense of dread.
The doctors pulled up Will's MRI scan. They pointed to dark spots in an area of his brain called the basal ganglia, which are involved in the coordination of movement.
Based on this pattern, the doctors diagnosed Will with a rare condition called Leigh syndrome.
In a healthy person, they explained, structures called mitochondria serve as the power plants of cells. They take food and convert it into the energy that cells use. Because of a genetic defect, Will's mitochondria were not able to perform the conversion properly. As a result, his cells were dying.
"What can we do to fix this?" asked Doug.
Doctors explained that there was nothing to be done. The disease was progressive and there was no treatment or cure.
"You're going to see your son gradually lose his abilities until he eventually passes away," a doctor said.
Kasey asked what the disease's time span was, and they replied that it was highly variable but that they rarely saw children live past the age of 10.
"Our lives were shattered," said Doug. "One minute we had all these hopes and dreams for our child, and the next minute we've been given a death sentence."
It started with armadillos
Steven Gray grew up in Thomasville, Alabama, a small town where he spent his childhood walking through the woods and catching armadillos with his bare hands.
In one of his first scientific experiments, when he was about 12, he tagged armadillos by painting a yellow spot on their backs, loaded them into his parents' car and released them several miles away to see if they would come back. They did.
"This may be an unknown fact of armadillos: They are territorial," he said, gently poking fun at his early exploits.
At Auburn University, he won a prestigious undergraduate research fellowship and grew fascinated with genes and the origins of disease.
Just as he was preparing for graduate school, a teenager died in a gene therapy clinical trial, and the field came to a virtual halt. The news didn't dissuade Gray. "Part of this was me being naive," he said. "I was still excited about gene therapy. I was still undaunted."
In graduate school at Vanderbilt University, he focused on basic research, studying how cells replicate their DNA. But he returned to gene therapy as a post-doctoral fellow at the University of North Carolina. By then, scientists at UNC and elsewhere had found safer and more effective ways of delivering healthy genes to patients, and the field surged ahead once again.
Gray had always wanted to help people. But he never thought he would work directly with patients. That was for physicians, and he saw himself as a dedicated lab scientist. He liked to follow his curiosity, to make discoveries, to add, bit by bit, to the mountain of basic research that has led to medical breakthroughs like the ability to edit genes.
"Once you add that little piece of knowledge to human kind, it's there forever," he said.
Gray's career path shifted when he met a 4-year-old girl named Hannah Sames in Boston in the summer of 2008. Just a few months earlier, doctors had diagnosed her with a disease similar to Will's called Giant Axonal Neuropathy, or GAN. It was so rare that no one even knew its incidence rate. There are fewer than 100 known cases in the world.
Like Will, Hannah received a devastating diagnosis: she would likely not live past the age of 20. And, like the Wolebens, Hannah's parents dived into the medical literature and did everything possible to save their daughter.
Lori and Matt Sames started a nonprofit called Hannah's Hope and organized a symposium that brought together scientists to discuss what was known about GAN and possible therapeutic approaches to the illness.
Gray, then 30, attended on behalf of his UNC gene therapy lab.
Once he met Hannah, the two connected immediately. At the time, Hannah was at the earliest stages of GAN. She wore braces on her legs and walked a bit clumsily, but had no other visible symptoms. Her mother, Lori, recalled that Gray stopped to talk with Hannah between scientific sessions, squatting on the floor to meet her at eye level. She was the same age as Gray's oldest daughter, Aubrey.
"When I saw her," said Gray, "I saw my family."
Looking around the room, he could also see Hannah's future. Older patients at advanced stages of GAN had arrived at the symposium, one in a wheelchair and on a ventilator.
Gray's thoughts turned to what he would do in the lab if his own child's life were at stake.
That fall, Gray received the first grant that Hannah's Hope gave out and the first grant he'd ever received as the principal investigator of a project.
The Sameses and Gray launched a full-scale effort to develop a treatment for GAN. Until then, gene therapy had been delivered intravenously or by direct injection into the brain. Gray pioneered a way to inject the drug into spinal fluid, which shuttled more of the medicine to the brain and spinal cord.
The effort took six years and $6 million from Hannah's Hope. In 2014, the National Institutes of Health agreed to fund and host a clinical trial for the treatment that Gray had developed, and, in 2016, Hannah became one of 11 children to receive a first-of-its-kind gene therapy injection into her spine.
Gray and his colleagues reported at a scientific meeting in May that the intervention has been safe and well-tolerated and that there was evidence that disease progression had slowed.
Meanwhile, other families had heard about Hannah's Hope and began contacting Gray about their own rare conditions. He realized he had to make a choice.
"I had thought of myself as being a discovery scientist," he said. "Do I want to be doing science for the sake of doing science, or do I want to apply it to a directed cause? And I think the connections I've made with some of the families and the kids made it crystal clear to me that I knew which way I had to go."
He took on a half-dozen more neurodegenerative disorders, including Tay Sachs disease and others that few have heard of. He realized that the treatment he'd developed for Hannah could be customized for thousands of single-gene defects.
A new career path began to open. Where Gray once pictured running a small lab, mentoring students and making incremental discoveries, he now saw a way to directly impact the lives of very sick children.
He talks about the epiphany in a soft voice, his blue eyes widening. Dressed in a peach-colored polo shirt and jeans, he looks not much older than the newly minted Ph.D. he was when he first met Hannah.
Gray envisioned a list of all 6,000 rare diseases with no treatment, most of which are caused by gene defects and most of which kill their patients in a few short years. He pictured himself crossing out those diseases one by one.
'This is it'
In the summer of 2014, a few months after Will was diagnosed with Leigh syndrome, his legs began to weaken, his speech grew slurred, he lost his ability to swallow and required a feeding tube. But he remained the same curious, happy toddler his parents knew and loved.
Kasey spent that first year in shock, unable to discuss his condition without crying. She and Doug had heard about gene therapy but figured it was too far in the future to help Will.
Then, last September, at a meeting with their UT Southwestern neurologist, Dr. Juan Pascual, they heard that the university was launching a gene therapy center and that Gray would soon be joining the faculty.
"This is it," thought Doug. "This is what we've been looking for this whole time. And it's happening right here in Dallas."
Will and Kasey emailed UT Southwestern to ask when Gray would arrive and to gently lobby for the institution to pursue Leigh syndrome. Eventually, they got the email they were hoping for: an invitation to meet with Gray and his team.
They filed into a small office on the second floor of one of UT Southwestern's newest research buildings. There, they met with Gray and Dr. Berge Minassian, chair of pediatric neurology at UT Southwestern and director of its gene therapy center, and Darrin Goldin, who oversees development for the medical center.
Minassian gave them the good news: Leigh syndrome was a candidate for gene therapy.
The goal would be to load healthy, synthetic copies of Will's defective gene into viruses that had been stripped of their own DNA. Doctors would inject trillions of the viruses — contained in two tablespoons of liquid — into Will's spinal fluid, where they would circulate around his brain.
"It's sort of like you're dusting crops," said Gray.
The viruses would then latch onto cells and, using the viruses' natural biology, traffic the genes inside. Once inside the cell's nucleus, the gene would start to produce the proteins Will was missing.
Gray warned the Wolebens that they were not offering a cure but simply an experiment. They didn't know whether gene therapy would help patients with Leigh syndrome or whether it would be ready in time to help Will. All they could do was try it and see.
The Wolebens were elated. Now they would have to raise money to get the experiments going: $300,000 to launch the animal studies and, if those went well, another $1 million to $3 million for human trials, unless a drug company or the National Institutes of Health got involved.
Kasey used Google and Facebook to identify two other families with recently diagnosed children. Together, the families formed a foundation named for the defective gene at the root of their children's illness: Cure SURF1. As of July, the foundation has raised $125,000 toward its $300,000 goal, largely from friends, family and colleagues.
Gray and Minassian took on Leigh syndrome even though developing a treatment for the disease is a bit of a long shot. Before the Food and Drug Administration would let them test the treatment in children, they would have to show that it could rescue mice with the same condition. Yet mice with Will's genetic defect appear healthy, making it harder to show that gene therapy works for them. After consulting with colleagues as far away as Cambridge, England, though, Gray and Minassian believe they have figured out a way to make it work.
"If you were to look at it from the outside, you might have picked something different (to study)," said Gray. "But in a very practical way, when you have people that are very committed to driving the treatment forward, then it happens faster."
He and Minassian select diseases based on a combination of scientific merit and families' commitment to raising money and putting their children through clinical trials. In the ultra-rare disease world, finding patients for trials is no simple task, because there are so few candidates.
They say they empower patients to make their own treatments possible.
Some ethics experts see it in a different light. Jonathan Kimmelman, a bioethicist at Montreal's McGill University, said it's important for researchers and patients to collaborate on research of this caliber. "But asking patients to raise funds for their own clinical trials does not empower patients," he said. "It empowers the people with the most resources."
Turning to patients can also bypass the peer-review process in science, which helps ensure that researchers pursue projects that have the greatest chances of success and that have a maximum impact on society. "The priorities dictated by science may not be the same ones dictated by patients who are effective fundraisers," said Kimmelman.
He also worries about inflated expectations on the part of families. The vast majority of experimental treatments put into early-stage trials never demonstrate enough safety or efficacy to be approved by the FDA.
"The probability of benefiting is extremely remote, and burdens like extra clinical visits and blood draws are a foregone conclusion," he said.
Gray explains that there is no "magical, big pot of resources" that he can tap to fund his work.
In fact, the main pot of resources for medical research has shrunk relative to the number of scientists applying for grants. Michele Calos, a Stanford University geneticist and president of the American Society of Gene & Cell Therapy, said the National Institutes of Health, the primary source of medical research funding, used to honor about one-third of grant applications. Now it funds less than 20 percent. "If researchers could obtain funding more reliably," she said, "they wouldn't have to ask families to do this."
She adds that money flowing into medical research is a good thing, no matter the source, because it will advance knowledge.
Gray said he tries with every project to minimize the financial burden on families by applying for federal grants and courting pharmaceutical companies. Relying on families, at least early in the process, means he doesn't have to wait months for NIH grants to come through before launching his projects.
As for fair access to treatments, if and when the technique Gray develops goes into clinical trials, it will be available to other patients with Will's disease. Most of the costs would be covered by the trial's sponsor — the Cure SURF1 foundation, a federal agency or a drug company.
Finally, Gray and Minassian see their work as having broad social value.
Collectively, rare diseases outnumber any common disease, Minassian points out. And experts need to understand them before they can hope to tackle more genetically complex conditions like Parkinson's or Alzheimer's. "We need to learn about these single-gene defect disorders," said Minassian. "At the same time, we are trying to save the lives of kids who are going to suffer and die if we do nothing. So it's kind of a win-win situation."
Gray does see downsides to the patient-funding model. One of those is the speed with which he forces himself to work. The typical pace of scientific research is slow and deliberate. But he and his patients can't afford to work on a typical academic timescale.
"We have the faces of the patients in our lives every day," said Gray, sitting behind the desk of his still sparsely furnished office.
While most researchers conduct lab experiments step by step, Gray and his team do everything in parallel. They conduct safety and toxicology tests on mice while also manufacturing the experimental drug. The risks are mainly financial — winding up with a batch of drugs that will never be used in patients, for example — but it's a risk families are willing to bear.
Leaning against a wall, not yet mounted, is a cork board with photos of a dozen of the families he has worked with. A mother and daughter blow out birthday candles. Brothers in wheelchairs pose by the water. Some patients were in the GAN clinical trial. Others, all children and young adults, have died waiting for treatments.
"In some ways it's harder, just because everything has to be yesterday," he said. "It's a breakneck pace. And no matter how fast you move, you always feel like you should be going faster."
A budding hockey player
On a recent morning at Keystone Pediatric Therapy in McKinney, Will rolled his wheelchair up to a child's play table.
His speech therapist, sitting in a miniature chair across from him, had him practice a series of "t," ''k" and "g'' sounds that he tried his hardest to produce. As his muscles have weakened, his speech has become slurred and he's had trouble pushing out enough breath to form sounds.
"All his language is there," said Jaclyn Brede, the speech language pathologist he works with at Keystone. "He understands everything. He just can't get it out."
Will needed occasional breaks to rest, so he signaled thumbs up or thumbs down each time Brede asked if he was OK to continue.
At physical therapy in a room next door, he gleefully whipped bean bags through the air to strengthen his arm muscles.
Back home, he resumed the activities of a normal 6-year-old, playing with his sister and parents. He took a break on the sofa with Doug, who has worked from home since Will's diagnosis. He arranged World Cup soccer stickers in a book, his thin legs crossed in front of him.
Soon, he was up again. His parents work to keep him physically active, his muscles working as much as possible.
Will, Doug and Lauren, 4, launched a raucous game of indoor hockey. Ice hockey is Will's favorite sport and he roots for the Dallas Stars and the Pittsburgh Penguins, a favorite team of one of his beloved older cousins.
Lauren guarded the goal while Doug, in bare feet, maneuvered Will's wheelchair around the living room floor. Will expertly wielded his hockey stick and slammed the puck repeatedly toward Lauren, who blocked nearly every shot. She was not about to give her older brother any breaks.
Will, far from discouraged, kept trying and trying until he finally got one past her and then another. He cheered, raised his arms and stick above his head and grinned, exposing a wide gap left by two missing baby teeth.
That night, as Kasey slept upstairs in a twin bed beside Will's, Doug was back at his computer. Now he had a new mission. With a potential treatment in his sights, he had to find something, anything, that would help Will live long enough for Gray to save him.
Information from: The Dallas Morning News, http://www.dallasnews.com
Texas couple races against time to treat son's rare disease
McKINNEY, Texas (AP) — Ever since doctors diagnosed his son with a rare disease, Doug Woleben has spent every evening on his computer, searching for a way to save the 6-year-old's life.