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Evangelina Vaccaro playing beneath pier at the beach

A decade after gene therapy, children born with deadly immune disorder remain healthy

Evangelina Vaccaro playing beneath pier at the beach

Evangelina Vaccaro playing beneath pier at the beach

By Sarah C.P. Williams

Over a decade ago, UCLA physician-scientists began using a pioneering gene therapy they developed to treat children born with a rare and deadly immune system disorder. They now report that the effects of the therapy appear to be long-lasting, with 90% of patients who received the treatment eight to 11 years ago still disease-free.

ADA-SCID, or adenosine deaminase–deficient severe combined immunodeficiency, is caused by mutations in the gene that creates the ADA enzyme, which is essential to a functioning immune system. For babies with the disease, exposure to everyday germs can be fatal, and if untreated, most will die within the first two years of life.

In the gene therapy approach detailed in the new paper, Dr. Donald Kohn of UCLA and his colleagues removed blood-forming stem cells from each child’s bone marrow, then used a specially modified virus, originally isolated from mice, to guide healthy copies of the ADA gene into the stem cells’ DNA. Finally, they transplanted the cells back into the children’s bone marrow. The therapy, when successful, prompts the body to produce a continuous supply of healthy immune cells capable of fighting infections. Because the transplanted stem cells are the baby’s own, there is no risk of rejection.

Kohn and his team report in the journal Blood that of the 10 children who received the one-time treatment between 2009 and 2012 as part of a phase 2 clinical trial, nine have continued to remain stable. The study follows a 2017 paper, also published in Blood, on the initial success of the treatment in those nine children.

“What we saw in the first few years was that this therapy worked, and now we’re able to say that it not only works, but it works for more than 10 years,” said Kohn, senior author of the study and a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. “We hope someday we’ll be able to say that these results last for 80 years.”

While not yet approved by the Food and Drug Administration, gene therapy for ADA-SCID represents a potentially life-changing option for children who otherwise must undergo twice-weekly injections of the ADA enzyme — an expensive and time-consuming treatment — or find a matched bone marrow donor who can provide a transplant of healthy stem cells.

10 years after: Assessing and refining gene therapy for ADA-SCID

Of the 10 children who received the therapy between 2009 and 2012, most were babies; the one older child, who was 15 at the time, was the only participant whose immune function was not restored by the treatment, suggesting the therapy is most effective in younger children, Kohn said.

The other nine children were successfully treated and have remained healthy enough that none have needed enzyme replacement or a bone marrow transplant to support their immune systems in the years since.

However, the researchers did find significant immune system differences among the successfully treated children roughly a decade on. In particular, they observed that some had a nearly hundred times more blood-forming stem cells containing the corrected ADA gene than others, as well as more copies of the gene in each cell.

Those with more copies of the ADA gene in more cells had the best immune function, Kohn noted, while some of those with lower levels of the gene replacement required regular infusions of immunoglobulins, a type of immune protein, to keep their systems fully functional. More work is needed, he said, to understand the best way of achieving high levels of the gene in all patients.

“What these results tell us is that there’s a formula for optimal success for ADA-SCID, and it involves correcting more than 5 to 10% of each patient’s blood-forming stem cells,” said Kohn, who is also a distinguished professor of microbiology, immunology and molecular genetics and a member of the California NanoSystems Institute at UCLA. “The relationship between the levels of gene-corrected cells and immune system function has never been shown so clearly before.”

The researchers also found that in some children’s stem cells, the treatment disturbed genes involved in cell growth — a phenomenon seen in other studies of similar gene therapies. While over time this could potentially lead to the improper activation of the growth genes, turning the cells cancerous, Kohn noted that none of the patients in the clinical trial had this problem.

Still, that safety concern is one of the reasons Kohn and his colleagues are developing a new ADA-SCID gene therapy using a different type of virus to deliver the corrected ADA gene that is much less likely to affect growth genes. This newer approach successfully treated 48 of 50 babies who received the therapy in clinical trials at UCLA, University College London and the National Institutes of Health. And while the approach used a decade ago may no longer remain the top candidate for FDA approval going forward, Kohn says its enduring success is encouraging for the field in general.

“Knowing that a gene therapy can have this lasting effect in ADA-SCID for more than a decade is important for our path forward as we develop new gene therapies for this and other diseases,” he said.

The research was supported by an FDA Office of Orphan Products Development award, the National Gene Vector Biorepository, the National Human Genome Research Institute intramural program, the National Institutes of Health Clinical Center and the California Institute for Regenerative Medicine.

This article originally appeared in the UCLA Newsroom.

Rachelle Crosbie-Watson in her lab at UCLA.

Curing a deadly childhood disease, sharing her love of science, and a sleek ’68 Corvette drive this biochemist

Rachelle Crosbie-Watson in her lab at UCLA.

Rachelle Crosbie-Watson in her lab at UCLA.

 

Spend a brief amount of time with biochemist Rachelle Crosbie-Watson and you’ll quickly realize that “drive” is one of her favorite words.

With equal enthusiasm, she’ll describe studying “the small molecules that drive life,” and her 1968 convertible Corvette being “a blast to drive.”

The symmetry is hard to miss: Crosbie-Watson drives a classic muscle car to UCLA, where she studies the biochemical reactions that drive muscle cell functions. Her lab is hotly pursuing new drugs that one day may halt the progression of a deadly childhood muscle-wasting disease, allowing kids with the disorder to lead normal lives.

The popular digital network, Mashable, recently profiled Crosbie-Watson for its “How She Works” series, which shadows a day in the life of women professionals working in fields related to science, technology, engineering and math, or STEM.

With her fiery pink hair, charismatic personality and affinity for high-speed cars, Crosbie-Watson doesn’t resemble most people’s vision of a biochemist. But her talent for crafting fresh approaches to solving thorny scientific puzzles is exactly what makes her such an ingenious scientist.

“What I love most about my job is the opportunity to be creative,” Crosbie-Watson said. “To solve the biggest problems in the world, we need individuals with different viewpoints to chime in. Working with people who are learning science for the first time — coupled with the thrill of discovery — makes for a really exciting recipe.”

Crosbie-Watson wears a lot of hats. Starting July 1, she will chair the integrative biology and physiology department in the UCLA College. She is also a professor of neurology in the David Geffen School of Medicine at UCLA, and the education liaison for the Center for Duchenne Muscular Dystrophy at UCLA.

In a sunny space in the Terasaki Life Sciences Building, Crosbie-Watson oversees a window-lined laboratory staffed by young researchers. Reflecting her appeal as a mentor and role model, 14 of the 17 are female.

Her team is intent on finding a cure for Duchenne muscular dystrophy, a deadly genetic disease that slowly weakens every muscle of the body. Striking 1 in 5,000 boys, the disorder typically reveals itself in frequent falls near age 4, reliance on a wheelchair by age 12, and teenage loss of the ability to move the upper arms. Young men with Duchenne frequently die in their 20s, when their heart and lung muscles stop pumping, leading to organ failure.

“Duchenne is a horrible disease that steals young boys’ childhoods and takes young men in the primes of their lives,” Crosbie-Watson said.

The disorder is caused by a genetic error that blocks the production of dystrophin, a protein that normally protects the membrane around muscle cells as they contract and relax. Left susceptible to damage from daily wear and tear, the unprotected cells eventually begin leaking their contents into the surrounding tissue, progressively weakening the muscle until it stops working.

Her lab’s earlier studies in mice gave Crosbie-Watson an insight into how to halt that process.

“We found that boosting levels of a molecule called sarcospan restored the membrane’s ability to protect muscle cells,” she said. “Sarcospan strengthens the muscle’s capacity to withstand the forces of daily use, diminishing the harm caused by Duchenne.”

Led by graduate student Cynthia Shu, the lab began scanning thousands of potential drugs to identify ones able to elevate cellular levels of sarcospan. Three years and 200,000 candidates later, the team has identified a handful of promising contenders for preclinical testing.

Crosbie-Watson applies the same imaginative approach she follows in research to her teaching. To educate the next generation of scientists about Duchenne, she created a virtual-learning course that invites Duchenne patients to describe what it’s like to live with the condition.

Open to undergraduate students enrolled at any University of California campus, the online course vividly illustrates the human toll and financial cost of the disease on patients and their families. Crosbie-Watson is currently developing a graduate program that explores muscle cell biology with an emphasis on translational research.

In recognition of her contributions to campus-wide education, Crosbie-Watson earned the 2013 UCLA Chancellor’s Distinguished Teaching Award. This year she received the UCLA Life Sciences Faculty Excellence Award for education innovation.

“Getting other people excited about science energizes me,” Crosbie-Watson said. “I love teaching young researchers how to put things in context and keep their eyes on the big prize.

“Science is something you can do for a really long time,” she added. “Asking the next question never ends, it drives you forward. The chase is the motivation; that’s what makes research so addictive.”