Gene therapy works for ‘Bubble Boy’ disease

August 24, 2011

Gene therapy works for ‘Bubble Boy’ disease


Nine years after getting gene therapy for a rare, inherited immune system disorder often called “bubble boy disease,” 14 out of 16 children are doing well, researchers report.

The children were born with severe combined immunodeficiency disease (SCID). They got an experimental gene therapy in the U.K.

A new report shows that nine years later, 14 of the 16 children had working immune systems and were leading normal lives.

“These children, who would have died very young without treatment, are participating in life as fully as their brothers and sisters,” researcher H. Bobby Gaspar, MD, PhD, tells WebMD. “Most of them are going to school, playing ball, and going to parties.”

Few Treatment Options for SCID

Children with SCID carry genetic defects that prevent their immune systems from working. Without treatment, most die from infection in their first two years of life.

One exception was David Vetter, a Texas boy born in 1971. Vetter lived in a specially constructed sterile plastic bubble from birth until his death at age 12. He became famous as the “bubble boy,” and his story made many people aware of SCID for the first time.

For decades, the treatment has been to get transplants of blood-forming stem cells from the bone marrow of matched siblings or other donors who have healthy immune systems.

Such transplants can effectively cure the disorder. But only about one in five children with SCID have a perfectly matched donor.

Bone marrow from partially matched donors can also be used. But those mismatched transplants are much more risky. About one in three children who have them die from the procedure.

About a decade ago, researchers discovered a way to manipulate a patient’s own genes to manufacture the missing part of the gene needed to make the immune system work.

Since that time, gene therapy has been used to treat dozens of children with SCID, says UCLA researcher Donald B. Kohn, MD, who did not participate in the U.K. study.

How the Children Fared

“The big picture here is that almost 10 years down the line, all of these children are alive and 14 of 16 have been able to correct their immune systems,” Gaspar says. “With [mismatched] transplants, we would have lost two to four of them.”

The 16 children with SCID who got the gene therapy ranged in age from 6 months to 3 years. Four of them had the ADA-deficiency type of SCID. The other kids had the X1 form of SCID. Those are the two most common types of SCID.

For most of the children, gene therapy was a success. But one boy who had the X1 form of SCID developed treatment-related leukemia. The complication was not unexpected, Gaspar says, because four children with the X1 from of SCID in a French study had developed leukemia after getting the gene therapy.

Gaspar says researchers learned from those cases and have modified the treatment in hopes of reducing the risk for patients with the X1 form of the disorder.

Kohn says gene therapy should be considered the treatment of choice for children with ADA-deficient SCID who do not have perfect bone marrow donor matches. It may prove to be a better choice for patients with perfect donor matches, too, he says.

As for the X1 form of the disease, Kohn says it remains to be seen if the new approach to gene delivery works and has less risk of leukemia.

Lessons learned from the SCID trials have spurred studies to find effective gene-based treatments for other blood cell diseases, including sickle cell anemia, Kohn notes.

“The history of gene therapy research can be summarized as, ‘Two steps forward and one step back.’ We retrench, we learn, and then we move forward again,” he says.

“Twenty years ago, nothing was working,” Kohn says. “Ten years ago, these treatments started to work, but with complications. The hope is that the next decade will bring highly effective treatments with few complications.”

By Salynn Boyles

Reviewed by Laura J. Martin, MD


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‘Bubble Boy’ Kids Living Normally After Gene Therapy: Study

August 24, 2011

‘Bubble Boy’ Kids Living Normally After Gene Therapy: Study

By Amanda Gardner
HealthDay Reporter

WEDNESDAY, Aug. 24 (HealthDay News) — More than a dozen children with so-called “bubble boy” disease are alive and well, with functioning immune systems, nine years after undergoing gene therapy to correct their disorder, researchers report.

Most of the patients attend school with other children, something that probably would have been fatal without treatment.

“The promise of gene therapy is being fulfilled, at least for these diseases, where a number of patients are walking around in good health because they had gene therapy,” said Dr. Donald Kohn, professor of microbiology, immunology and molecular genetics and pediatrics at the University of California, Los Angeles.

The disorder — severe combined immunodeficiency (SCID) — compromises the immune system so severely that children can’t fight off normally innocuous infections. The condition is rare, and the term “bubble boy” was coined after a Texas boy with the condition lived in a germ-free plastic bubble.

Only boys inherit the gene in question, and many born with SCID die in infancy.

Two studies published Aug. 24 in Science Translational Medicine detail the results of the gene-modifying treatment. Kohn wrote a perspective piece accompanying the studies.

Traditionally, the only treatment for SCID was stem cell transplantation in which immune cells from a matching donor are transferred to the patient. But it’s difficult to find matching donors and, even then, the patient’s body may reject the transplanted cells.

With gene therapy, clinicians remove the patient’s own bone marrow, isolate the stem cells, correct the gene and reinsert it into the patient, explained William J. Bowers, associate professor of neurology at the University of Rochester Medical Center in Rochester, N.Y.

The two current papers detail the success of gene therapy in two groups of patients: 10 boys with X-linked SCID (SCID-X1); and six with ADA-SCID, which involves a slightly different gene mutation. All were between 6 months and 39 months old.

Gene therapy successfully treated four of the six ADA-SCID patients.

All the SCID-X1 children recovered, although one developed leukemia. That boy is currently in remission, but leukemia has been a problem with previous gene therapy trials.

Last year, French researchers reported that eight of nine male infants born with SCID-X1 had recovered as a result of gene therapy. Unfortunately, almost half developed acute leukemia, one of whom died.

The virus vector used in this earlier trial inadvertently activated an oncogene, which led to the development of the leukemia, researchers said.

The latest research circumvented this problem by using a different virus vector.

“A cloud was thrown over the field several years ago and they’ve solved it nicely,” said Dr. Darwin Prockop, director of the Texas A&M Health Science Center College of Medicine Institute for Regenerative Medicine at Scott & White in Temple, Texas. “Very probably this can be used for other genetic diseases.”

“This field came on with huge promise, then hit a few bumps and now . . . we’re starting to see more and more of these successes,” added Bowers.

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Glaxo Turns its Eye to ‘Bubble Boy Disease’ in Rare Disease Push.

October 18, 2010

Glaxo Turns its Eye to ‘Bubble Boy Disease’ in Rare Disease Push.

By Jeanne Whalen
GlaxoSmithKline strengthened its focus on rare diseases today by targeting one of the rarest: ADA severe combined immune deficiency, one form of so-called “bubble boy disease.”

ADA-SCID, which affects only about 350 children worldwide, is caused by a genetic defect that leaves kids without a functioning immune system, making them extremely vulnerable to infection and early death.

The standard treatment today is a bone marrow transplant, which gives the patient new stem cells that, with luck, will start producing the blood cells needed to make the immune system function. But closely matched donors are hard to find, and the patient’s body often rejects the transplanted cells.

Glaxo has licensed an experimental gene therapy from two Italian institutions that aims to fix the stem cells in the patient’s own bone marrow. Stem cells are removed and a healthy gene is inserted before the cells are returned to the body. Glaxo and its partners believe that using the patient’s own cells will reduce the risk of rejection.

The therapy has demonstrated “potential” in phase 1 and 2 studies, Glaxo says. The drug giant and the two institutions — Fondazione Telethon and Fondazione San Raffaele — plan to see if the same technique might be used in treatments for a range of other rare diseases, from metachromatic leukodystropy to Wiskott-Aldrich Syndrome. (Trials for those two diseases are now recruiting patients.)

The partnership is part of Glaxo’s growing push into the rare disease market, Marc Dunoyer, global head of rare diseases, told journalists on a conference call today. About 70% of the 6,000-8,000 rare diseases that have been identified have genetic origins, and many have clear molecular targets. As Dow Jones Newswires reports, Dunoyer said his rare disease unit will focus on four areas: metabolism, immuno-inflammation, central nervous system and hematology. DJN notes that “he declined to say how much money the division would spend or whether acquisitions were part of its drug development strategy.”

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Bubble baby gene therapy ‘worth the risk’

September 30, 2010

Bubble baby gene therapy ‘worth the risk’

By Philippa Roxby Health reporter, BBC News

‘Bubble boy’ Rhys Evans turns 10

Rhys Evans was born with no functioning immune system and no resistance to infection.

Even simple germs like a cold could have killed him.

Today he is celebrating his 10th birthday and he is a healthy, happy schoolboy.

Thanks to ground-breaking gene therapy treatment at Great Ormond Street Hospital, Rhys has a working immune system and is able to live a normal life.

But it was not always that way. Rhys, from the village of Nelson in Caerphilly county, was born with a fatal genetic disorder called X-SCID – X-linked severe combined immunodeficiency.

He suffered recurrent chest infections from the age of four months and was eventually admitted to hospital with pneumonia.

Doctors finally diagnosed X-SCID, a very rare disease which affects only two or three children in the UK each year.
Continue reading the main story
“Start Quote

Gene therapy has the potential to tackle disorders where there was no treatment at all before.”

End Quote Professor Adrian Thrasher Great Ormond Street Hospital

In 2001 Rhys began his gene therapy treatment.

Nine other boys with the same disorder have now been treated in the same way at the London hospital.

“Most of the children have recovered good immunity,” says Professor Adrian Thrasher, consultant immunologist at Great Ormond Street Hospital.

The disease is often known as ‘baby in the bubble syndrome’, because affected babies have to be kept well away from any infections.

Rhys’s mother Marie Evans explains: “Before Rhys’s treatment he was cut off from the outside world in a super-clinical room where he could only be visited under strict supervision.

“He was so weak he couldn’t even hold his head up,” she said.
New instructions

During gene therapy, a working copy of the defective gene is placed in the child’s own bone marrow cells using a virus and these are then returned to the child’s body.

The hope is that the modified cells grow and help restore the child’s immune system.

Without the treatment, Rhys would have died before his second birthday.

In 2007, however, Great Ormond Street hospital announced that one of the 10 children receiving gene therapy had developed leukaemia.

Subsequently, there were headlines questioning the treatment programme.

But leukaemia was “an acknowledged risk” of the treatment for this specific group of diseases, says Professor Thrasher, which they were prepared for.

It is thought the implanted gene was planted next to, and switched on, a gene that causes cancer.

Other similar studies in France and the US had also experienced the development of leukaemia in a small number of patients.

“We have learnt why that’s happened,” says Prof Thrasher. “We’ve now redesigned the vector which carries the gene into the cells and the risks are much, much lower.”
Assessing the risk

“We must stack this risk alongside the risk of normal treatment and the dangers of a mismatched bone marrow transplant. Leukaemia is a very serious illness but it can be treated and success rates now exceed 80%.”

The conventional treatment for a child with X-SCID is bone marrow transplantation.

This can have excellent results when a fully matched donor is found, but results are less successful with a poorer match.

And only one third of X-SCID patients will have a fully matched donor.

Great Ormond Street is the only hospital in the UK doing this type of gene therapy for children with X-SCID and similar genetic disorders.

“There is no real difference between this and any other form of medicine,” Professor Thrasher explains.

“There will be side effects but you have to balance the risks against the benefits.

“Gene therapy has the potential to tackle disorders where there was no treatment at all before, for inherited diseases particularly.”

And how is Rhys now?

“We still keep an eye on him as because he’s growing, his immune system sometimes needs a helping hand to keep up,” replies Prof Thrasher.

“But we’re delighted to see he’s doing so well eight years after his treatment.”

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How an in-gene-ious treatment saved Rhys

September 30, 2010

How an in-gene-ious treatment saved Rhys

Sep 30 2010 by Kathryn Williams, South Wales Echo

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TEN-YEAR-OLD Rhys Evans will be celebrating his birthday today by thinking of someone else – the charity that helped save his life.

Rhys, from Nelson, was the first child in Britain to be cured by gene therapy after he was born with SCID – a severe combined immunodeficiency – which meant he had no resistance to infection. Left untreated, the condition would have killed Rhys before his second birthday – even simple germs like a cold could have killed him.

Rhys’s mum and dad, Marie and Mark, still remember the time they spent with their little boy in Great Ormond Street Hospital, who now is like any other 10-year-old, building Lego and teasing his little brother Alex.
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Mark said: “Rhys was just three months when he kept getting ill all the time, just after Marie stopped breastfeeding him, the doctors tried lots of different drugs, but nothing would work.

“The doctors at the University Hospital of Wales in Cardiff were stuck so they rang Great Ormond Street, who wanted him to come up.”

Rhys was sedated for weeks until the paediatric doctors proposed trying gene therapy on him, instead of the usual bone marrow transplant.

Despite initial concerns, Marie and Mark decided to go ahead with the therapy, and now Rhys, who attends Ysgol Bro Allta in Ystrad Mynach, is 99% well, although he needs daily injections to keep his immune system strong.

Mark said: “After the therapy he was kept in isolation, we had to wear special boots, mask, hat and gloves and enter a special room to get rid of all the dust and germs from our clothes.

“After Rhys came out of hospital, we couldn’t really take him out to shopping centres or parties, but he was able to start nursery and then full-time school.

“He has had chicken pox but was able to fight that off himself, which is really pleasing. We have been a little bit overprotective, but we’ve had to be.”

But Rhys, who turns 10 today, is as active as any other child his age, attending after-school dance classes, and even has a keen interest in science and playing with his Lego.

He said: “Sometimes I have to put the cream on my legs when I have the injections, and it’s a little bit scary having a big needle, they may stop in the summer so I can play longer outside.”

Jeans for Genes is the UK children’s charity that aims to change the world for children with genetic disorders. Now in its 15th year, Jeans for Genes has raised a staggering £35m.

Jeans for Genes Day is tomorrow and invites everyone to wear their jeans to work or school in return for a donation

The money raised will help fund vital care and support services for children and families affected by genetic disorders, as well as research.

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Points of Light in Gene Therapy Renaissance

July 29, 2010

Points of Light in Gene Therapy Renaissance

By Ricki Lewis

Patient success stories drive gene therapy forward.

July 29, 2010 | WASHINGTON, DC—Like the mythical Phoenix that springs anew from its ashes, gene therapy shows signs of re-emerging with a stockpile of safer and more efficient viral vectors. At the annual meeting of the American Society of Gene and Cell Therapy last May*, optimism was palpable.

The excitement peaked when 9-year old Corey Haas walked onstage at the Presidential symposium. His physician, Jean Bennett, professor at the F. M. Kirby Center for Molecular Ophthalmology at the University of Pennsylvania, announced: “I’d like to introduce the youngest person ever to speak at ASGCT.”

Until his gene therapy in September 2008, Corey was headed for blindness from Leber congenital amaurosis type 2 (LCA2). Today he plays baseball and just recently saw fireflies for the first time. He calmly answered questions from an astonished audience, and afterwards was mobbed by awed scientists, some in tears.

Earlier that day, Corey and his parents joined other emissaries of recent advances in gene therapy at a news conference. It was sparsely attended because across town, Craig Venter had just announced that he had artificially created life.

LCA2 is caused by mutation in the RPE65 gene. “RPE65 helps to recharge vitamin A, and without it, there is no vision. The gene therapy idea was simple—deliver the gene to the retinal pigment epithelium,” which hugs the photoreceptors, said Bennett. The pediatric clinical trial at Children’s Hospital of Philadelphia treated 12 patients between the ages of 8 and 24 in one eye. All improved.

The target disease most like the metaphorical phoenix is severe combined immune deficiency (SCID). Gene therapies for two treated forms had problems. First was ADA deficiency, tried on a 4-year-old in 1990. Her restored health could have been due to concomitant enzyme replacement. And gene therapy for SCID-X1 (“bubble boy disease”) worked, but caused leukemia.

Don Kohn, director of the University of California Los Angeles human gene medicine program, discussed new gene therapy trials for both forms of SCID using safer vectors. A trial to treat 20 boys with SCID-X1 is underway in Paris, London, and three sites in the U.S., using a “self-inactivating” retroviral vector. And for ADA deficiency, Kohn’s group is using the chemotherapeutic busulfan to clear space in the bone marrow for replacement cells, and using a lentivirus (HIV), which works in non-dividing cells, carries bigger genetic payloads, and integrates more efficiently than past vectors. “To date, four of eight patients have benefited clinically, living at home and doing well,” he said. And that’s without enzyme replacement.

In the second row at the press conference sat three young women who catalyzed gene therapy for their family’s disease, adrenoleukodystrophy (ALD), the genetic disorder portrayed in the film Lorenzo’s Oil. When Nathalie Cartier-Lacave arrived, the four women embraced. Cartier-Lacave is director of research at INSERM in Paris.

The ALD protein normally admits very long chain fatty acids into peroxisomes, where they are degraded and used to make myelin, which insulates neurons. Behavioral symptoms rapidly progress to seizures, blindness, and incapacitation. “The only treatment, a stem cell transplant, takes 12 to 18 months for progression to stop,” said Cartier-Lacave, but is risky. Gene therapy, also using HIV, exploits the fact that the brain cells affected in ALD (the microglia) come from bone marrow. The first two patients made headlines in fall 2009, after they had been making normal ALD protein for many months, as MRIs tracked remyelination. “There was no problem with HIV or immunity or insertion into a gene that causes leukemia,” said Cartier-Lacave.

Eve (Salzman) Lapin said that after her son Oliver was diagnosed with ALD in 2000, genetic testing found that one brother and a cousin had also inherited the disorder. Sisters Amber Salzman (an executive at GlaxoSmithKline at the time) and Rachel Salzman (a veterinarian) launched Stop-ALD, uniting researchers for a clinical trial. “They did everything shy of following us into the men’s room,” jokes Jim Wilson, professor of pathology and laboratory medicine at the University of Pennsylvania, who helped the sisters.

Lapin had the final word at the news conference. “The legacy of Oliver’s life and death is that gene therapy will be a better way to treat ALD and other terrible diseases.”

Ricki Lewis is the author of The Forever Fix: The Rise, Fall and Rebirth of Gene Therapy and the Boy Who Saved It, to be published by St. Martin’s Press.

*American Society of Gene and Cell Therapy, Washington, D.C., May 19-22, 2010

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Efficacy of Gene Therapy for X-linked Severe Combined Immunodeficiency

July 22, 2010

Efficacy of Gene Therapy for X-linked Severe Combined Immunodeficiency

Salima Hacein-Bey-Abina, Pharm.D., Ph.D., Julia Hauer, M.D., Annick Lim, M.Sci., Capucine Picard, M.D., Ph.D., Gary P. Wang, M.D., Ph.D., Charles C. Berry, Ph.D., Chantal Martinache, M.Sci., Frédéric Rieux-Laucat, Ph.D., Sylvain Latour, Ph.D., Bernd H. Belohradsky, M.D., Lily Leiva, Ph.D., Ricardo Sorensen, M.D., Marianne Debré, M.D., Jean Laurent Casanova, M.D., Ph.D., Stephane Blanche, M.D., Anne Durandy, M.D., Ph.D., Frederic D. Bushman, Ph.D., Alain Fischer, M.D., Ph.D. and Marina Cavazzana-Calvo, M.D., Ph.D.

N Engl J Med 2010; 363:355-364July 22, 2010


The outcomes of gene therapy to correct congenital immunodeficiencies are unknown. We reviewed long-term outcomes after gene therapy in nine patients with X-linked severe combined immunodeficiency (SCID-X1), which is characterized by the absence of the cytokine receptor common γ chain.


The nine patients, who lacked an HLA-identical donor, underwent ex vivo retrovirus-mediated transfer of γ chain to autologous CD34+ bone marrow cells between 1999 and 2002. We assessed clinical events and immune function on long-term follow-up.


Eight patients were alive after a median follow-up period of 9 years (range, 8 to 11). Gene therapy was initially successful at correcting immune dysfunction in eight of the nine patients. However, acute leukemia developed in four patients, and one died. Transduced T cells were detected for up to 10.7 years after gene therapy. Seven patients, including the three survivors of leukemia, had sustained immune reconstitution; three patients required immunoglobulin-replacement therapy. Sustained thymopoiesis was established by the persistent presence of naive T cells, even after chemotherapy in three patients. The T-cell−receptor repertoire was diverse in all patients. Transduced B cells were not detected. Correction of the immunodeficiency improved the patients’ health.


After nearly 10 years of follow-up, gene therapy was shown to have corrected the immunodeficiency associated with SCID-X1. Gene therapy may be an option for patients who do not have an HLA-identical donor for hematopoietic stem-cell transplantation and for whom the risks are deemed acceptable. This treatment is associated with a risk of acute leukemia. (Funded by INSERM and others.)

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