Trial Gives Hope for a Cure Cure

by Teresa Carey, National Institutes for Health - Reprinted with Permission

It’s Teatime

and doctors, researchers, and patients are at the table. They celebrate a decade of work and launch the first in-human gene therapy trial for children suffering from a rare and devastating disease, GM1 gangliosidosis.


Cyndi Tifft opened a bag and pulled out one of the items inside: a teacup. It was painted with colorful flowers, and gold trim adorned the rim. Written across the bag, in an eight-year-old’s scrawl, was “For Dr. Grandma. Thank you. Love, Jojo.”

Tifft was getting ready for Jojo’s tea party of a lifetime. What would happen after, while young Jojo napped, would be the most significant—a culmination of a decade of work and a new life for someone with a devastating disease. Jojo was about to receive the first experimental gene therapy treatment for the rare disease, GM1 gangliosidosis.

A faulty gene halts a critical process

Dr. Tifft, a geneticist at the National Genome Research Institute, first met Jojo in 2016. Jojo and her mother, Lei, arrived at the NIH Clinical Center with their tea set when they volunteered to take part in Tifft’s natural history study. For 10 years, Tifft followed 35 children with GM1 gangliosidosis to see how the disease developed, hoping to gain insight into treatment options.

During her first visit, Jojo renamed all her doctors. She dubbed her six-and-a-half-foot-tall neurologist, “Dr. Big Shoes.” By the end of the week, she called Tifft, “Dr. Grandma.” When Tifft hears that name, she beams.

When Tifft met Jojo, she was walking, talking and writing. Now, three years later, Jojo needs help standing, speaking and just about everything else. She has a disease that attacks nerve cells in the brain, rendering them useless, one by one. When Jojo was born, GM1 gangliosidosis was already wreaking havoc on her neurons. At the time, no one knew.

Jojo inherited the genes for GM1 gangliosidosis from her mother and father. Though they are both healthy, they each have a mutated GLB1 gene. With only one mutated copy, they are considered carriers, and are unaffected. GM1 gangliosidosis manifests in people with two copies of the mutated gene. Jojo inherited one from each parent. This inheritance pattern is called autosomal recessive. The odds of two carriers meeting and passing on their mutated GLB1 gene are slim; on average, only about one in 100,000 people has GM1 gangliosidosis.

Molecules, called gangliosides, align neurons and act as signals. They tell the body how to do things like talk, walk, or chew. As they age, gangliosides are broken down in the lysosome, the recycling center of a cell. After old ones are dismantled, new gangliosides are built.

Within the lysosome is a team of enzymes, which are like workers in the recycling plant. Each has a specialized role. Together, they break down complex molecules, like gangliosides, that the cell no longer needs.Imagine the workers in an assembly line. Their job is to take apart a ganglioside made of sugars and fats. The first worker cuts off the first sugar, the next worker cuts off the next sugar, and so on. The process is smooth and methodical. But people with GM1 gangliosidosis aren’t producing the first worker—the enzyme that starts the process. Without that enzyme, the recycling effort is halted before it even begins. A backlog of gangliosides creates a blockage that overwhelms the system. New signaling molecules aren’t built, neurons stop functioning, and ultimately processes like walking, talking, and even breathing slow down and eventually stop.

Jojo and Dr. Cyndi Tifft host tea parties every time Jojo has an appointment. The tradition extended to the entire team on the day of the gene therapy trial.

How to deliver a new gene

Tifft had set the tea tray in front of Jojo. Under her lab coat she wore a long blue gown. But nothing compares to the striking red and gold gown and tiara Jojo wore. Her mom, Lei, wore a matching red skirt.

“Red signifies energy,” Lei said. It was an energy everyone felt reverberate through the room.“

Cake for breakfast is the best,” Tifft said. Her voice carried over the chatter of more than 30 people packed into the tiny hospital room. Jojo sat on the edge of the bed supported by a caregiver as Tifft offered her a bite of mango cake. She washes it down with orange juice from a teacup. The tea party has been a tradition for the pair since Jojo started seeing Tifft. Only this tea party was different. On this day, Jojo would receive the first in-human gene therapy that could be an effective treatment for GM1 gangliosidosis. The people surrounding her spent the past decade in a massive effort leading up to this day.

In the 1970s, medical and veterinary researchers joined forces when they found a cat that had GM1 gangliosidosis. The veterinary researchers said the disease was as relentless in cats as it is in humans. The cats with GM1 gangliosidosis lost their ability to walk or even stand.

The two researchers from the Auburn University College of Veterinary Medicine, Doug Martin ’89, Ph.D., and Heather Gray-Edwards ’07, DVM, Ph.D. [now an assistant professor and gene therapy researcher at the University of Massachusetts], said that after meeting Tifft they attempted a matching natural history study in cats. They found that cats responded to the disease in the same ways humans did. The disease progression in their cat study paralleled the progression in the humans of Tifft’s study. Cats made the ideal animal model for the first gene therapy test.

Miguel Sena-Esteves, Ph.D., associate professor of neurology at the University of Massachusetts Medical School, was instrumental in creating the gene therapy vector—an unwitting virus that would deliver functioning copies of the defective GLB1 gene to the cat’s brain cells.

A virus delivers its genetic information into the cell.

Viruses are ambitious. They try to take over their micro-world by delivering their genes to the host and replicating themselves. Viral infections are generally viewed negatively. Take the flu virus, for example: it moves into the respiratory tract, binds to the surface of cells, and inserts genetic information, causing fever and aches.

Because of their drive to rampantly conquer and sow their seed, could viruses do the same work, except deliver helpful genes? Sena-Esteves attempted exactly that by removing the guts of a harmless virus and replacing them with a healthy gene that is programmed to make the missing enzyme. The new gene will use the cell’s machinery to make the much-needed enzyme. But they only get one chance to get it right. Once the virus enters Jojo’s body and delivers the gene, she will start making antibodies to fight it. That rules out the option for a “re-do,” because her body will have built a defense army to neutralize the virus vector.

The gene therapy vector was successful in safely treating the cats with GM1 gangliosidosis. With the new gene, the lysosome factory worked without a glitch and neurodegeneration was no longer a concern.

This demonstrated to the U.S. Food and Drug Administration that they were ready to test the treatment on humans in a clinical trial. Now, Edwards, Martin, Sena-Esteves, and everyone else in the room were on the edge of their seats anticipating the trial.

“Let’s hope we didn’t spend the last 10 years doing something that will only work in animals,” Sena-Esteves said lightheartedly, then adds, “How many times have we cured cancer in mice? Thousands.”

But Sena-Esteves said his confidence level is high. “The only regret that I have is it took so long to get here,” he said, adding that had their work moved along sooner, then maybe they could have helped Jojo before the disease progressed as far as it did. Still, Sena-Esteves recognizes how this trial will impact future children with GM1 gangliosidosis. “What this child did is open the path for everyone,” he said.

Bits of mango tea cake covered Jojo’s face as one-by-one she playfully gave everyone a “mango hug,” sprinkling crumbs on their cheeks.“

Thanks a lot, Cyndi,” Martin said to Tifft, the instigator and only one who escaped the mango hugs. Tifft laughed. No one worried about the sugary crumbs because, to them, this day represents more than a decade of work, cross-continental collaboration, and new hope for those suffering from this devastating disease.

“This day is right up there with my wedding day and the birth of my kids,” Tifft said.

Waking up to a second chance

With the lights out, the crowd quietly gathered in the hallway. Jojo was falling fast asleep in the hospital bed.

It was time.

Two nurses measured and prepped the perfect amount of the gene therapy vector. They double checked the protocol and measurements twice over. Jojo was napping in her hospital bed, still wearing the party dress and clutching a stuffed animal.

The nurses moved past the crowd and entered the dark room. Everyone looked at each other, whispering, “I think we should wait out here,” and “There isn’t anything to see anyway. She is just napping.” But no one could help themselves, and one-by-one, all 30 people tiptoed into the room.

Everyone watched Jojo as she received the gene therapy vector. It was delivered into her body through an IV drip while she slept. People snapped pictures, celebrated, laughed, cried, and embraced each other. The party continued, quietly.

When Jojo awoke, she was the same girl with the same neurological challenges. Tifft will monitor Jojo for the next five years, looking for changes in her cognitive abilities. Tifft said, “Theoretically, humans are born with all the neurons we will ever have. We aren’t regenerating new ones.” At the very least, she expects that Jojo’s condition will stabilize. This outcome would be a huge success and enough to move from the clinical trial phase to a new drug approval in two years. However, there was also a feeling of optimism in the room. Many anticipated that the treatment could reverse some of Jojo’s decline, helping her regain the ability to walk or talk.

“She is still developing. The cats finish developing at eight weeks, but Jojo’s brain continues to develop until she is 18 years old. I’m hopeful that we can reverse a lot of this stuff,” said Gray-Edwards.

Tifft has plans to launch a broader clinical trial this fall. Her team will select eight children to undergo the same treatment and monitoring protocol as Jojo. Then, if all goes as planned, the team will have an effective treatment for GM1 gangliosidosis. Children could have their genes tested in the womb or at birth. With one dose of the gene therapy, they could avoid a lifetime of decline.

“I keep pinching myself,” Lei said. “I’ve dreamed about this hundreds of times. Then I wake up and reality is not great. I think Jojo deserves a chance.” Lei has been a driving force for ensuring this clinical trial would happen for Jojo and the next children. She knows precisely what is at stake. That morning she asked her daughter, “Jojo, do you know why we are here?

”Despite the short, inarticulate sounds Jojo makes in response, Lei understood her reply.

“Hope,” Jojo said.

Auburn’s Pivotal Role in the Search for a Cure

For more than four decades, Scott-Ritchey researchers at the Auburn CVM have sought a cure for GM1 gangliosidosis, a rare, neurodegenerative disease found in animals and humans. Today, Dr. Doug Martin ’89, professor in the Department of Anatomy, Physiology and Pharmacology, and a team of his fellow Scott-Ritchey Research Center scientists believe they have found an effective treatment for the disease. His research, an extension of work begun in the 1970s by mentors Dr. Henry Baker ’60 and the late Dr. Nancy Cox ’75, is a gene therapy to produce enzymes found missing in GM1 and Tay-Sachs-related cases.

Martin and Tifft embrace on the day of the gene therapy trial.

Building on the original research, Dr. Martin and his team—which includes University of Massachusetts Medical School researchers Dr. Miguel Sena-Esteves and Dr. Heather Gray-Edwards ’07, DVM, previously a post-doctoral student and faculty member at Auburn—have successfully extended the life expectancy of cats by more than five times compared to non-treated GM1 cats with the use of gene therapy, a non-harmful viral vector to produce enzymes missing in GM1 and Tay-Sachs-related diseases. In December 2018, the gene therapy product was licensed to Axovant Gene Therapies Ltd. (Nasdaq: AXGT), a clinical-stage company developing innovative gene therapies.

Less than a year later, the first human clinical trial is underway. This gene therapy is the first treatment developed at and licensed by Auburn University to go to human clinical trials.

“There is no question now the disease can be treated successfully,” Dr. Martin said. “We have seen how the treatment has worked in cats with the disease and how it has extended their lives as healthy animals.”

The Auburn researchers have been inspired throughout their long journey toward a clinical trial by two Alabama children with GM1 gangliosidosis, Porter Heatherly of Auburn and Clara Bragg of Hoover, who now resides in California. Porter died Nov. 10, 2016, but not before putting a human face on the disease for the research team and for everyone at the Auburn CVM who came in contact with him. Both sets of parents, Michael and Sara Heatherly and Ryan and Jenny Bragg, have become part of fundraising efforts to help find a GM1 cure.

Dr. Martin was at the National Institutes of Health in Bethesda, Md., recently to watch the first child in the clinical trial receive the treatment. “The treatment is a testament to a parent’s refusal to give up,” he said, “but also speaks to the thousands of family members who have searched for a cure for this disease. The families have been the motivation of our research.”

He said being at the NIH to watch the first human treatment was a pinnacle moment in his life, professionally and personally. “This treatment is extremely promising because it has worked well in GM1 mice and cats, and it is delivered by a single IV injection that takes less than an hour. We’re hopeful that the treatment makes a real difference for patients and their families. As the trial progresses and more patients are treated, we’ll have a good idea of whether the gene therapy helps children as much as it has helped the animals. That is certainly what we’re hoping for.”

“This research and the clinical trial are the perfect example of what we call ‘One Health,’ meaning that as we advance the health of animals we also are searching for ways to improve the health of people,” said Dean Calvin Johnson ’86. “Almost every human disease has an animal counterpart, and one of the very important missions of our College is to understand animal diseases to the point where we can identify similarities with human illnesses. Because when we find those similarities, we can identify where diseases are vulnerable and collaborate with other researchers to find cures.

“This progress in treating GM1 gangliosidosis is one of the greatest achievements, research-wise, in the 127-year history of the College,” he added. “We are very proud and committed to the Scott-R itchey Research Center to continue this work.”

How You Can Help

Those interested in helping the fight against GM1 and similar diseases can make a donation to support GM1 research through the Auburn University Foundation. Gifts are designated to “Porter’s Fund” in honor and memory of the late Porter Heatherly and should be made out to Auburn University Foundation and sent to the attention of:

Auburn University Foundation

Attn: Gift Processing

Re: Scott-Ritchey GM1 Research

317 South College Street

Auburn, Alabama 36849