By Rose Cahalan in Features, July | August 2017 on July 1, 2017 at 9:00 am |

From left, Jenny, Tanner, Clara, and Ryan Bragg. Credit: Tiffany Roach

In the video, Clara Bragg and her mom, Jenny, are sitting underneath the family Christmas tree.

Clara, 2, wears a pink bow in her wispy blonde hair. She smiles before turning to play with a pile of colored blocks, her mouth hanging open in concentration. Its an idyllic family scene, complete with Claras brother, Tanner, 5, sitting next to her under the warm glow of the tree. Then in the next scene, the whole family is seated together on the couch, Jenny with a squirming Clara on her lap while her husband, Ryan, MBA 10, holds Tanner on his knee. Hello, he says, looking into the camera. My name is Ryan Bragg, and this is my family.

By now, the Braggs are used to introducing themselves to the world. Theirs is a story theyve told hundreds of timesin YouTube videos like this one, on the local news, on websites and Facebook posts and forums, and at dinners, parties, and fundraisers. Its not an easy story to tell, but after eight months of practice, they are pros. So they dont hesitate when theyre asked to tell it one more time.

Clara was born in April 2014, and the Braggs were over the moon, according to Jenny, BS 03. Theyd always wanted a boy and a girl, and her arrival made their family feel complete. She was an energetic baby with lots of personality. She was constantly moving, Jenny says. Always wiggling, always wanting to be in the mix. A very social kid. She hit all her developmental milestones, including saying mama and dada. But then, around 14 months, she stopped saying them. She also couldnt quite get the hang of walking and often fell.

The Braggs started to wonder if something was wrong. Clara had always been tall for her age; maybe her balance just hadnt caught up to her height. They took her to doctors and physical therapists near their home outside Birmingham, Alabama. Each test and exam led to more referrals, shrugs, and vague reassurances. We saw more specialists than I can count, Ryan says, and every single one of them said a different version of the same thing. Yeah, there are some delays, but its not a big deal. Either shell outgrow it, or well handle it with therapy.

After a year of these appointments, the Braggs enrolled Clara in a study that involved a full genetic workup. A genetic counselor and a geneticist called them in for a meeting to discuss the results. They were pretty direct about it, Jenny remembers. He told us what was going to slowly happen, and that she probably wouldnt

She pauses, and theres a long silence before Ryan starts talking. The geneticist told them that Clara had a disease called GM1 gangliosidosis that would cause her to slowly lose her ability to walk, talk, and eat; to suffer breathing difficulties, seizures, deafness, and blindness; and eventually, to die before her 10th birthday. And, Oh, by the way, just go home and watch that happen because you probably only have a few years left, Ryan says. It hits you like a ton of bricks. Theres no escaping the devastation and the lump in your throat and the knots in your stomach.

The genetic counselor handed them a three-page printout with more information. They learned that GM1 is extremely rare, affecting 1 in 200,000 children, and that there is no cure. It was pretty obvious that theyd done the medical equivalent of Googling this thing, Ryan says.

Which is exactly what the Braggs did when they got home. They found medical journals and forums and websites and pictures of kids transforming from smiling babies into bedridden toddlers with breathing tubes. They also came across the website of Doug Martin, a research scientist and professor at Auburn Universitys College of Veterinary Medicine, who studies GM1 and related neurodegenerative diseases. Ryan fired off an email. We are just beginning to learn about and try to understand this disease, but have learned of the research you and your team have done Would it be possible to meet? he wrote. This is quite a shock to us and were starting from scratch.

***

On the first and second floors of the Scott-Ritchey Research Center at Auburn University in Auburn, Alabama, there are more than 100 cats. As research animals go, they live a comfortable life: A full-time staffer is dedicated to their care, playing with them and making sure they get enough exercise. They nestle into towel-lined boxes, scamper up to high perches, and bat at toy mice with their paws.

Back in 2003, this scene looked very different. As kittens, the lab cats developed minor tremors that soon progressed into full-body shakes. Soon they couldnt stand or walk; an employee had to lift them into the litter box. These cats were born with GM1, and gene therapy saved their lives.

The results have been tremendous, Martin says. They arent completely normal, but if I put them in a room with a bunch of normal cats, it would be hard for you to pick them out. They have only a slight hind-limb weakness.

Before Martins team injected an engineered virus directly into the cats brains, their life expectancy was 8 months. Now some cats in the colony are 7 years old. The average survival increase is six times, which is really unheard of, he says.

GM1 falls within a category of rare diseases known as lysosomal storage diseases. Lysosomes are the digestive system of the bodys cellssacs of enzymes that break down molecules and send them elsewhere in the body for recycling. Kids (and cats) with GM1 dont make enough of a critical enzyme, and without it, the recycling process comes to a halt. That leads a protein called GM1 ganglioside to build up to toxic levels in the brain and other parts of the body.

The earlier GM1 strikes, the more severe it is. Clara was diagnosed with Type 2, the late infantile type. Most kids with that variant of the disease die before they finish elementary school.

Researchers at Auburn have been studying GM1 for more than 30 years. Martins predecessor and graduate school mentor, Henry Baker, kept the cat colony in his garage as he experimented with treatments, such as injecting the missing enzyme. Baker eventually succeeded in treating the cats peripheral organs, but he couldnt get past the blood-brain barriera security system of sorts that protects the brain from foreign invaders. After decades of work, Martin and his colleagues have overcome that obstacle by engineering a virus that can pass through the barrier. An injection directly into the brain is no longer requireda simple one-time IV dose will do the trick. Once the virus is in the body, it starts churning out the enzyme that kids like Clara need, Martin says.

***

On a Saturday afternoon in August, Martin was at home when he saw Ryan Braggs email. It was only the latest of dozens of desperate messages hes received from parents over the years. Now that were closer to a clinical trial, I hear from parents every couple of weeks, Martin says. The Braggs were the second GM1 family hed met in Alabama. A year earlier, Martin had gotten to know Porter Heatherly, a toddler with the most severe type of the disease. I had never watched a child deteriorate on a monthly or weekly basis the way I did with Porter, he says. Heatherly died in November 2016.

Martin called the Braggs back within a half-hour. Awe and respect are audible in Ryans voice as he recalls the conversation. I was impressed that he called at all, Ryan says. Hes a busy guy at a top university. He called to offer his condolences and to give us a glimmer of hope. In the coming months, they would meet Martin and visit his lab.

The Braggs learned that Claras diagnosis had come at a fortuitous time. Martin was already close to setting up a clinical trial in humans. After decades of working on the science, he felt confident in the gene therapys potential to help kids as it had cats. Now the biggest barriers were bureaucracy and funding.

GM1 is one of more than 7,000 rare diseases affecting at least 25 million Americans. More than half of rare disease patients are children, and 80 percent of rare diseases are genetic. In the medical community, these are sometimes called orphan diseases for their lack of funding and attention. With many of these conditions affecting maybe a few dozen people or fewer, there just cant be enough funding from traditional sources, says Mary Dunkle, vice president of educational initiatives for the National Organization for Rare Disorders. In many cases, most or even all of the research funding is raised by the patient community.

In the case of GM1, the most costly part of a clinical trial would be manufacturing the virus for the gene therapy. A much larger quantity of the virus is needed for a human trial than in animals, and scaling it up isnt cheap. Martin estimated the total manufacturing cost at $750,000.

That was all the Braggs needed to hear. They set out to raise as much money as they could as quickly as possible. In order to be eligible for the trial, Clara would still need to be fairly early on in her disease progression. The clock was ticking.

Theres something unimaginably cruel about busy working parents, still reeling from traumatic news, having to take on what amounts to a second full-time jobbut the Braggs felt they didnt have a choice. They threw themselves into their new roles as GM1 advocates and fundraisers. In a sense, they were as well-prepared as anyone could be. Jenny studied corporate communications at UT, so messaging and social media marketing were familiar territory. Shed planned events in her former job at the Texas General Land Office, experience that would come in handy for the dozens of fundraisers ahead. Ryans MBA from McCombs taught him how to tap into his network and hit financial goals. Jenny quit her job to focus on caring for Clara and fundraising, while Ryan juggled work as a finance director at PepsiCo with the second shift at home.

Jenny rattles off a litany of tactics. Weve had a fashion show, a movie theater event, all kinds of dinners, silent auctions, raffles, a St. Patricks Day campaign called Buck for Luck, she says. We did charity beers, a wiffle ball tournament, a daddy-daughter dance, and a crawfish boil. The whole spectrum, really. The A Cure for Clara Facebook page has more than 1,300 likes.

Credit: Magen Davis

Their work has paid off. In less than a year, the Braggs have raised more than $1 million for GM1 research. Those funds have directly contributed to making a clinical trial possible. Theyve knocked it out of the park, Martin says. Ryan and Jenny are amazing. For me, its been so great to not have to worry about funding as much. Its enabled me to focus on the science.

It takes six months to make the viral vector for the clinical trial, and that process cant begin until the scientists have shown they can pay for it. With a typical National Institutes of Health grant taking 18 months to get funded, Martin says the trial process would be months and months behind without the Braggs donation. Now things are well underway, and the researchers are hoping the trial will take place in December 2017 or January 2018.

At the end of my conversation with the Braggs, I ask if theres anything other stories have gotten wrong. Everyone feels compelled to say were searching for a cure, Jenny says. But its such a key component to our campaign that were actually trying to fund the cure, not find the cure. Weve already found it.

***

Is that really true, though? While the cat research is promising, there is no guarantee that animal results will translate directly to humans, and many questions about the disease remain unanswered. Martin is more measured. Cure is a really strong word, he says. I feel very strongly that our work will benefit the human patients. That said, until you actually try it, you just dont know for sure. He adds, I know that the parents are desperate. The pressure we feel is enormous.

One important unknown: whether the gene therapy in the trial will reverse symptoms or only halt the diseases progression. The results of animal studies have been mixed on that front, Martin says. Im hopeful there will be some recovery of function, he says, but nobody knows the answer at this point.

If the clinical trial has outstanding results, its possible the FDA will broaden it to include more patients. Should all go well, parents may then petition the agency to release the treatment under a provision called compassionate use. Also called right-to-try, compassionate use gives terminally ill patients access to new and experimental drugs. This legal loophole has saved lives, but its not without risks.

In 2014, the family of Josh Hardy, a 7-year-old cancer patient, ran a successful social media campaign to get him a drug through compassionate use. Media coverage at the time attacked the pharmaceutical company, Chimerix, for withholding the medicine. Eventually the company and the FDA relented, and the Chimerix CEO was fired. The drug saved Hardys life. But what if it hadnt? Had Hardy died after taking the drug, it would have been banned. That could potentially result in the deaths of innumerable future patients, bioethicists argued at the time, and we have an ethical responsibility to them, too. (Hardy died two years later of complications from his cancer.)

In a critical op-ed for nbcnews.com, NYU medical ethicist Arthur Caplan argued that Hardys campaign went viral because he was a cute and cuddly childmuch like Clara, with her blond curls and cherubic smile. His parents, like the Braggs, are privileged, well-connected, and media-savvy. What about patients who lack those advantages? Another ethicist, George Annas, told Harpers that this whole community going-on-a-vengeance thing is not a decent way to get health care for your child.

Then theres the name forever on the minds of Martin and all gene therapy researchers: Jesse Gelsinger. Gelsinger died at age 18 during a botched gene therapy trial at the University of Pennsylvania in 1999. That was a tragedy, and it shut down our field for years, Martin says. We want to give these kids a chance, but we also dont want to do anything that could shut down a promising field. The FDA is always slowing us down, and although that can be very frustratingultimately, its a good thing. (Martin stresses that gene therapy has advanced significantly since 1999, and that the type of therapy used in the GM1 trial is as safe as it gets.)

Theres one final hurdle: drug pricing. Even if the trial goes well and the therapy is eventually approved, drugs for rare diseases tend to be extremely expensive. Thats because pharmaceutical companies are profit-driven, and its hard to turn a profit if your market consists of only a few dozen patients. The Orphan Drug Act of 1983 gave companies a financial incentive to make drugs for rare diseases, but prices have ballooned out of control: In 2014, the average orphan drug cost $118,820 per patient per year. That means families campaigning may not end even once theyve found and funded the cure. In 2016, the FDA approved a new drug for spinal muscular atrophy, another progressive and often fatal genetic disease in childrenbut it costs $750,000 a year, and insurance companies dont always cover it. Dozens of pleading GoFundMe pages have popped up.

Long-term, there absolutely needs to be a comprehensive look at reform for both the pricing and access issues, says Dunkle, the rare diseases advocate. Social media is powerful. It levels the playing field, gives families with rare diseases a way to make their voices heard. But sick kids shouldnt have to rely on Facebook to get life-saving care.

***

In April, the Braggs are gearing up for one of their biggest events yet: Claras third birthday party. The fundraising goal is $10,000; there will be VIP sponsors, a silent auction, live music, and cake with pink frosting. The next month, theyre planning a Zumba fun-raiser. Talking about their work, Ryan and Jenny sound hopefulbut also completely and utterly exhausted.

The balance is not great right now, Jenny admits. Its not great in terms of any aspect of our life and relationships and family. She and Ryan struggle to strike an impossible balance between constantly working to give their daughter a future and simply enjoying the time they have with her today. I wouldnt be able to live with myself if I wasnt putting everything I had into this, she says. But once this next fundraiser is over, weve said we need to take a break.

The Braggs worry about their older child, Tannerwith all the attention on his sister, is it even possible to give him a normal childhood? Hes only 5, and they arent sure how much he understands about the situation. They make a point to fit in his T-ball practices and take him to playdates. We try to prioritize him, to spend one-on-one time, Jenny says. But its a lot of energy that goes into Clara.

The night before our interview, Jenny says, Tanner blurted out a question as she was tucking him into bed. Is Clara going to die? She paused, taken aback, then decided she might as well tell him the truth: She will if we dont get her medicine in time.

Illustration by Jonathan Bartlett

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A Cure for Clara - The Alcalde

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