Waiting for a miracle cure

Kyle and Christin Webb had their first baby on March 13, 2014. They named her Mabry Kate. And for the first few months of their daughter’s life, she seemed like any other happy, healthy baby girl.

At 3 months old, she was just learning how to babble and giggle responsively.

Then, all of a sudden, Mabry Kate stopped smiling. Her playful reactions stopped, too. She started throwing up after every bottle and losing weight fast.

By the time she turned 4 months old, Mabry Kate weighed less than at her two-month checkup. But none of the doctors the Webbs consulted had any definitive answers.

Slowly, they started running tests and ruling out different conditions. At first, the Webbs felt that was a good sign—until they realized it probably meant their daughter had something very serious and even more rare.

Finally, the Webbs took Mabry Kate to a group of specialists at Cincinnati Children’s Hospital Medical Center, about four hours from their home in Knoxville, Tenn. A few days later, they returned a diagnosis: Krabbe disease, a rare inherited disorder causing progressive muscle paralysis, cognitive decline, and eventually, death.

Fewer than 5,000 people in the United States have Krabbe disease. It has no cure and only one existing treatment to slow its advance.

Krabbe disease is one of an estimated 7,000 to 10,000 rare diseases, depending on how these conditions are defined. The vast majority have genetic causes. Diagnosing and treating these disorders is exceptionally difficult because any given condition may only have a handful of known patients in the world. An estimated 95% of rare diseases don’t have any effective treatments available.

But now, the advent of the elegant and efficient gene-editing tool CRISPR-Cas9 offers a glimmer of hope. While the technology raises ethical concerns related to the specter of designer babies, experts say CRISPR therapies targeting nonreproductive cells don’t raise the same alarms as embryo editing and could be a lifeline for people suffering from rare diseases.

Researchers around the globe are racing the clock to develop treatments for millions of people—mostly children—battling debilitating hereditary conditions like Krabbe disease. Still, lab research and clinical trials take time, and that’s exactly what many patients don’t have. About 30% of children with a rare disease die before they turn 5 years old.

While they wait, families like the Webbs are left to grapple with unanswered questions and exist in an unimaginable tension: learning to celebrate and embrace each new day even as they live under the shadow of a fatal diagnosis.

MABRY KATE suffered from the more aggressive infantile onset form of Krabbe disease—a condition that’s usually fatal by age 2. Doctors told the Webbs their daughter’s condition had worsened too much for her to benefit from a stem-cell transplant, the only available treatment to slow the disease’s effects.

For months, the Webbs had been desperate for an answer about what was wrong with their baby girl. Now, they had an answer—a devastating one they couldn’t do anything about.

That’s all too common for families dealing with rare genetic diseases. Dr. Jimmy Lin is the founder and president of the Rare Genomics Institute, a nonprofit focused on helping rare disease patients. Lin said there are few medical experts and very little existing research available because these cases are so rare. Getting an accurate diagnosis can often take as long as five or 10 years.

Lin and his team try to speed up this timeline by helping patients access the latest genome sequencing technology. But even then, it’s still difficult to pinpoint exactly which genetic variations are causing a patient’s symptoms. “Everybody is a different 3 billion-piece puzzle,” Lin said.

Lin estimated the diagnostic success rate for this type of genetic mapping is still only about 30%. Many patients never discover the root cause of their suffering. And even if they do, they often don’t have any existing treatment options. Since patient populations are so small, drug developers simply don’t have the same financial incentive to invest in cures.

But, while each rare disease may not individually affect many people, altogether about 300 million people worldwide suffer from one of these conditions.

While the Webbs searched for a diagnosis, they refused to dwell on the worst-case scenario. “We never really let it sink into our brains that we might lose her,” Kyle said. Then, they came face to face with that devastating, gut-­wrenching certainty. On top of that, Christin had just found out she was pregnant again.

Since Krabbe disease is genetic, the baby in her womb had a 25% chance of inheriting it, too.

Yet, somehow, in the midst of her fear and grief, Christin felt God speak to her. She said it was one of the few times in her life she heard His voice clearly and directly like that. “You’ve never been in control,” she recalled. “I’m the one in control, and I have your family in my hands.”

Those words steadied her even as everything seemed to spiral out of control. Three months later, just before Christmas, the Webbs received back the test result for Owen, the baby in Christin’s womb: positive for Krabbe disease.

Meanwhile, Mabry Kate’s condition continued to deteriorate quickly. The muscles in her arms and legs grew tight and spastic, her tiny hands balled into fists. Her eyes started flitting back and forth uncontrollably. She started struggling to breathe and had to be put on oxygen and a feeding tube.

Doctors told the Webbs Mabry Kate’s hearing and vision were fading, too. But they don’t think those senses ever fully deserted her. They put up a Christmas tree with twinkling lights, and their baby girl would stare at it with wide eyes alive with wonder.

That tree was still up a month later, when Christin started getting her little girl ready for a father-daughter dance with Kyle. She gave Mabry Kate a bath, carefully tugged on a polka dot dress, and painted each of her tiny fingernails.

But as Christin placed the finishing touch—a little hair bow—Mabry Kate started gasping for air. She’d struggled with breathing episodes before, but this time was different. She just couldn’t seem to recover.

Christin started to panic. “Please don’t take her! Please don’t!” she remembers screaming as she tried desperately to help Mabry Kate catch her breath again.

Just then, Kyle walked in the door. He had been away buying flowers and a corsage, but he came straight home when Christin called him. Right behind him, Christin’s parents had arrived to take pictures before the dance. Her dad called 911.

At the hospital, Kyle cradled his daughter in his arms. He had a playlist of love songs he played for Mabry Kate every morning. Now, he played it one last time. Together, father and daughter waltzed around the hospital room.

For months, Kyle had been wrestling with why God would allow such suffering in his daughter’s life. But then, as he felt her soul leave her tiny body, he didn’t question anymore. “As beautiful as she was, I know she wasn’t there anymore,” he said. “And that she did go on to someplace better.”

DIRECTLY AFTER Mabry Kate’s funeral, the Webbs packed up and moved to Durham, N.C. “We really didn’t even have time to grieve,” Christin said. “We pretty much buried her and left.”

They focused all their attention on trying to save Owen’s life.

Moving close to Duke University Hospital provided the best hope for getting Owen the treatment his sister had been unable to receive. People with Krabbe disease have a mutation in the GALC gene, which keeps their bodies from producing an important enzyme needed to break down toxins and prevents nerve damage.

A stem-cell transplant provides the patient a fresh supply of cells rich in this GALC enzyme. But in order to have the best chance of working, treatment needs to start as early as possible.

Less than two months after Mabry Kate’s death, Owen was born on March 30, 2015. He arrived a month early, and hospital staff immediately whisked him away to the neonatal intensive care unit to make sure his lungs had enough time to develop.

As soon as he was strong enough, baby Owen began his treatment with 10 days of grueling chemotherapy. The goal was to wipe out his immune system so his body wouldn’t attack the donor cells infused into his system, Christin explained. After that, Owen received his treatment: an IV infusion of blood.

Developing a medical treatment for a rare disease can take decades, a timeline surpassing the average lifespan for many patients, according to former National Institutes of Health Director Dr. Francis Collins. Although many Americans associate Collins with his handling of COVID-19 controversies, he is also an accomplished geneticist whose research team identified the genetic cause of cystic fibrosis in 1989.

That discovery paved the way for drugs that have significantly extended the average lifespan for people with cystic fibrosis. But that was just one genetic disorder among thousands. Researchers didn’t have a scalable approach they could apply across the board, Collins said. That changed when CRISPR-Cas9 burst on the scene in 2012.

But delivering on CRISPR’s promise still requires research, money, and time. Right now, researchers are working on an estimated 150 active clinical trials of gene-editing therapies, but only Casgevy, a treatment for sickle cell disease, has entered general medical use.

Medical solutions such as this one target only somatic cells, any of the ordinary, nonreproductive cells making up 99.99% of the human body. Unlike germline edits that target eggs, sperm, or early stage embryos, somatic cell edits don’t pass on to future generations. And somatic cell therapies don’t require research on human embryos.

Because of that, Collins argues this type of gene editing doesn’t raise any new ethical concerns. “They are basically a very high-tech way of providing the kind of treatment which we’ve in the past done with things like drugs,” he said.

Still, gene editing isn’t without its risks. Scientists often use viruses to deliver the CRISPR gene editor to targeted cells, and those can cause strong reactions in some patients. In 2022, 27-year-old Terry Horgan died from a deadly immune system response to a CRISPR treatment for his Duchenne muscular dystrophy.

And while CRISPR is more accurate than previous types of gene editing, it still comes with the risk of mistakes and genetic damage. Rare Genomics Institute President Jimmy Lin said editing the wrong gene can cause things like cancer and autoimmune diseases.

But Lin said it’s important to remember adverse events aren’t unique to CRISPR. All drugs come with risks and side effects. The whole point of clinical trials is to make sure new treatments are safe and effective for the patients who need them.

And that’s a goal worth pursuing—even for just a single person. “They are created in the image of God,” Lin said. “And that’s why we go all out to be able to help.”

BACK IN 2015, the Webbs spent four months in the hospital while Owen received his treatment. During this time, they met lots of other families going through the same process. Some children responded well to the treatment. But at least seven families lost a child that year.

Owen ended up in the intensive care unit with blisters on his esophagus—a side effect of chemo—which made it hard for him to breathe.

But, gradually, he started to grow stronger. Eventually, he was able to return home for four months of outpatient care. Today, Owen is an exuberant fourth grader who loves telling jokes and helping his mom coach basketball.

He still suffers from some Krabbe disease symptoms. Muscle tightness keeps him in a wheelchair most of the time and fine motor skills are a challenge. His speech is a bit delayed, too. But none of that slows him down, his parents say.

“He never questions anything,” Christin said. “He just loves life and rolls with it.”

At church and school, people make sure to include Owen in activities, Kyle said. He’s been able to play soccer and T-ball, too.

But some of those activities have become harder recently. Owen’s transplant isn’t a cure, and his parents have seen progression in his disease. The tightness in his legs has worsened, and he had to get Botox injections to help his muscles relax.

Owen’s treatment is relatively new, so it’s impossible to accurately predict what his life expectancy might be, Christin said. She knows some people with Krabbe disease still living in early adulthood. “But it’s just hard to say,” she said. “Every kid’s so different.”

Sometimes, the Webbs hear about a possible breakthrough therapy, and that gets their hopes up. But, so far, the stem cell transplant Owen already received is the only available treatment for Krabbe disease. When new health problems surface, Christin practices gratitude for just one day in which Owen is alive and happy.

“None of us are guaranteed tomorrow,” she said. “Even if we’re healthy.”