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Gene Therapy Restores Immunity for ‘Bubble Boys’

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April 17, 2019 -- In 1971, a boy was born in Texas with a rare genetic defect that robbed him of an immune system. With the help of NASA engineers, David Vetter lived for years inside a series of plastic rooms that protected him from infections, earning him the name “Bubble Boy.” He died at the age of 12.

Today, he might have been cured.

A team of scientists from Memphis, TN, San Francisco, and Seattle say they have treated 10 babies born with the same disease, called X-linked combined severe immunodeficiency, or SCID-X1.

The treatment -- a combination of chemotherapy and gene therapy -- appears to have restored normal immunity in most of the children. The oldest is now 3.

“It’s an exciting milestone because we can announce a cure,” James R. Downing, MD, president and CEO of St. Jude Children’s Research Hospital in Memphis, said at a news conference. He later tempered that remark by acknowledging that they don’t yet know how long the results will last.

“I think from a physiologic point of view, from a quality of life point of view, this is a cure. The question will become, ‘will it be a durable cure? Will it last 10, 20, 50 years for these children?’ Only time will tell,” he said.

Other experts who were not involved in the research said they were impressed with the study’s results.

“This is a wonderful advance,” says Howard Lederman, MD, a pediatric immunologist at Johns Hopkins School of Medicine in Baltimore. He says the new therapy, coupled with newborn screening for the disorder -- now available in all 50 states -- means doctors will be able to find and treat affected children before they get sick.

“This is really a complete change in what used to be a fatal disease,” he says.

It's advance that’s been decades in the making. The first patient treated with gene therapy in the United States was a 4-year-old girl who had a different form of the disorder, called ADA-SCID. She was treated at the National Institutes of Health in 1990.

The senior researcher on the study, Brian Sorrentino, MD, who survived cancer as a child and spent 2 decades coming up with the therapy, died before the study was published. He died of lung cancer that was a result of the radiation therapy he had as a child.

His life’s work is coming to fruition just as the field of gene therapy is exploding. The FDA received more than 200 new applications for gene therapies in 2018, nearly double the 106 it received in 2017, according to its Center for Biologics Evaluation and Research.

“At this point in time, innovation has been rapid, and we look forward to the continued research and development of these therapies in many areas, including autoimmune disorders, genetic disorders, metabolic disorders, heart disease, and cancer and HIV/AIDS,” Paul Richards, a public affairs specialist at the FDA, said in an email.

How the Therapy Was Done

For the trial, researchers at St. Jude used an HIV shell to carry a corrected copy of the defective gene into the babies’ blood-forming stem cells. The babies were then treated with a low dose of chemotherapy that cleared out space in their bone marrow so the repaired cells could take root and grow.

As the repaired stem cells multiplied, they began to crank out all the different kinds of immune factors that the body relies on to recognize and defeat threats -- including B cells, T cells, and natural killer cells. About 6 months after treatment, all the cells were present in normal amounts.

Not only were the cells being made, they also appeared to be communicating and keeping each other in check. As the number of T cells went up, for example, B-cell numbers when down, a sign that they were being properly regulated. Uncontrolled B-cell growth can lead to cancer, Lederman says.

So far, researchers say nine of the 10 babies in the study have normal immunity. One boy didn’t respond to the therapy and was re-treated. Researchers say he’s making better progress now.

Six of them have been able to stop getting monthly shots of immune-boosting antibodies. Three of them have gotten and responded to their childhood vaccines.

“The outcomes have been truly outstanding for our patients,” says study researcher Ewelina Mamcarz, MD, a researcher in the Department of Bone Marrow Transplantation and Cellular Therapy at St. Jude.

As good as all this sounds, it is a strategy that’s been tried before.

In 2000, French researchers, using a very similar approach, said they had cured boys born with SCID-X1. But 2 years later, some of the patients from the original study had gotten leukemia as a consequence of the gene therapy. Gene therapy trials in the U.S. and other countries were halted as researchers tried to figure out what went wrong.

Their conclusion was that the delivery system had accidentally turned on genes that sit next to the one that was repaired. The activated genes caused uncontrolled cell growth and cancer.

The St. Jude team says it guarded against this by inserting genetic insulators -- stretches of chicken DNA -- that keep the adjacent genes from being activated. They say that so far, they’ve not seen any signs of cancer.

‘His Whole Life Has Changed Around’

The advance has been life-changing for Omarion Jordan, a baby born in Indiana, one of the last states to screen for SCID at birth. He was born before screening began, so doctors missed his life-threatening condition at first. The disease affects 1 out of every 200,000 births.

“The first time he got sick, he was 2 months old. He had a bacterial infection, and he broke out in a nasty rash all over his body,” says his mother, Kristen Simpson.

Doctors diagnosed eczema and sent her home with creams and shampoos.

The infections got worse and worse. After his vaccines, when he was 3 months of age, the soft spot on his head began bleeding and oozing fluid. His head was covered with a “big nasty infected scab.”

“I was terrified,” Simpson says.

Finally, doctors did genetic testing and discovered the disorder. Omarion was sent to a hospital in Cincinnati for a bone marrow transplant, but doctors couldn’t find an eligible match, a common problem.

Only about 20% of children diagnosed with SCID have a sister or brother who’s a close genetic match for a bone marrow transplant. For children lucky enough to get those transplants -- which are considered the gold-standard treatment -- results are typically good, and they go on to live normal lives.

For others, bone marrow transplants from matches that aren’t perfect, but close enough, are able to restore some immunity, but the benefits from those transplants wane over time.

None of those options were available for Omarion, so he was brought to St. Jude for the trial. He and his mother have been there since November, but they expect to go home soon. His mother said he’s had no side effects from the treatment. He will celebrate his first birthday next week.

“His whole life has changed around. He’s able to go outside and do anything a healthy, normal baby can do,” she says.

It’ll Be an Expensive Therapy

The gene therapy has worked so well in the trial that it has already been licensed by Mustang Bio, which is based in Worcester, MA. Manuel Litchman, MD, president and CEO of Mustang, said he would approach the FDA to begin the approval process for the therapy, called MB-107, in July.

One looming question will be cost. Luxturna, one of three gene therapies now approved in the U.S., cures a rare form of blindness. It costs $850,000 for treatment of both eyes.

Litchman suggested that MB-107 would cost more. While he would not commit to a specific sum, he said the company was keeping an eye on a new gene therapy to treat spinal muscular atrophy, a disease that also kills babies if left untreated. That therapy, which will be marketed by Novartis if the FDA approves it, could cost as much as $4 million.

“We endorse the general trend in the industry to paying out over time for success. So if you think about a million-dollar therapy, it wouldn’t be a million dollars at the time of treatment; it would be a million dollars paid out, let’s say, $100,000 a year for 10 years for lifesaving therapy,” Litchman said.

He also said that patients wouldn’t keep paying if the treatment didn’t work.

“If the gene therapy failed after a year, then you’d just stop paying,” he said.

WebMD Health News Reviewed by Michael W. Smith, MD on April 17, 2019


James R. Downing, MD, president and CEO, St. Jude Children’s Research Hospital, Memphis, TN.

Howard Lederman, MD, PhD, professor of pediatrics; director, immunodeficiency clinic, Johns Hopkins School of Medicine, Baltimore.

Kristen Simpson, mother of trial patient Omarion Jordan, Fort Wayne, IN.

Manuel Litchman, president and CEO, Mustang Bio, Worchester MA.

Paul Richards, public affairs specialist, FDA Center for Biologics Evaluation and Research.

The New England Journal of Medicine, April 17, 2019.

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