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

linkback url http://www.bio-itworld.com/2010/issues/jul-aug/gene-therapy.html

‘Bubble Baby’ needs your help

July 25, 2010

‘Bubble Baby’ needs your help

Two-week-old Sanjana Praveen Shivanka, the ‘Bubble Baby of Sri Lanka’ needs your help, for slowly and surely time is passing and he may face the fate that his brothers were doomed to.

Like his two brothers whose graves are in the backyard of the home of their parents, K.B.N. Damayanthi and K.W.N. Neil Shantha, Shivanka is also affected by the Severe Combined Immuno-deficiency (SCID) Syndrome, a rare genetic disease for which he needs an urgent bone marrow transplantation which has to be performed in India.

SCID is also called ‘Boy in the Bubble Syndrome’ after the disease hit the headlines in the 1980s when David Vetter from Shenandoah, Texas, America who was born without a working immune system became famous when doctors placed him in a plastic isolation unit — since his brother had died earlier of this disease — to protect him from infections. David lived in this “bubble” for 13 years but died in 1984 following an unsuccessful bone marrow transplant.

Please make a contribution to the account set up by the Sunday Times to save Shivanka’s life:

linkback url: http://www.sundaytimes.lk/100725/Plus/plus_03.html

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.)

linkback url: http://www.nejm.org/doi/pdf/10.1056/NEJMoa1000164

New Gene Therapy Trials To Test Cure For Bubble Boy Syndrome

July 22, 2010

New Gene Therapy Trials To Test Cure For Bubble Boy Syndrome

New research sponsored at Children’s Hospital Boston will use gene therapy to fix the malfunctioning DNA of children with severe combined immunodeficiency (SCID), popularly known as the bubble boy syndrome. SCID cripples the immune systems of children with the disorder, leaving their bodies open to fatal infections. Bone marrow transplants have shown great success in treating SCID, but they are difficult to perform and unless they have a fully matched sibling, patients can wait years for an appropriate donor. Now a new wave of gene therapy is about to begin trials, sidestepping the transplant issues altogether by reprogramming a patient’s immune system to function properly.

Last year we covered gene therapy that cures the second most common subtype of the disease, SCID-ADA. The new study, sponsored by Dr. David Williams at Children’s, just got a green light from the FDA and is currently accepting patients. The research will apply a newly developed gene therapy retrovirus to the most common form of the disease: X-SCID, which involves a mutation along the IL2RG gene on the X chromosome. The gene therapy involves taking the patient’s own bone marrow, upgrading the cell’s DNA with a functional version of the gene, and reintroducing the altered marrow.

SCID is an immunodeficiency disorder that results from a child having a defective version of one of several genes essential to producing lymphocytes (white blood cells). Without a functional immune system, the child is highly susceptible to viral and bacterial infection – without treatment, most children die within the first year of life. Sterile isolation (the infamous bubble) is necessary unless the disease can be treated in some way. Traditionally, SCID has been treated with a bone marrow transplant from a sibling or parent if one is a suitable match; if not, children often wait for years for a donation.

Approximately 1 in every 100,000 children born suffer from SCID. The disease can be caused by mutations along one of several genes, and these mutations are not always easy to screen for. Often, SCID is not diagnosed until several months after birth, once the mother’s antibodies are cleared from the body and the baby begins to develop recurring infections. Because X-SCID is due to a mutation along the X chromosome, female carriers are generally heterozygous and do not express the disease. Only males develop X-SCID.

Bone marrow transplants have been highly successful in treating SCID, especially when they are administered early in life. Ideally, a transplant would come from a full-match sibling; because not every patient has one, sometimes unmatched siblings or parents donate marrow. These transplants require drug treatments to prevent graft-versus-host disease, and are riskier to perform in infants. Transplanted cells usually do not produce antibodies, and so transplant patients require immunoglobulin injections for the rest of their lives. These complications make marrow transplants a frustrating treatment option for many families.

SCID gene therapy, step-by-step

This is where gene therapy comes in. Rather than replace a patient’s faulty marrow with someone else’s, gene therapy reprograms the patient’s own genome by inserting new DNA to fix broken genes. First, bone marrow samples are taken from the patient. Next, a vector (e.g. a virus or retrovirus) is used to insert DNA into the marrow cells; this genetic material binds with the patient’s own, upgrading their genome to include the missing gene. Finally, the marrow is reinserted into the patient, where it can generate the lymphocytes that SCID patients lack. There is no risk of graft rejection with a patient’s own cells, and there is no need to wait for an acceptable donor. Antibodies can even be produced by the upgraded cells, eliminating the need for immunoglobulin injections.

One risk of gene therapy is that the DNA is often inserted randomly into the patient’s own genome. If the added DNA is inserted into the middle of an important gene – say, a gene that normally controls cell division – it can disrupt that gene’s function and result in cancer. Gene therapy for X-SCID has been controversial since 2005, when five children in Europe got leukemia from the retrovirus used in experimental treatments.

Since then, the Transatlantic Gene Therapy Consortium – an international collaboration between multiple institutions – set about completely redesigning the vector used to upgrade the patient’s genome. The retrovirus used in the current study is the first X-SCID treatment to be approved by the FDA since 2005, and underwent extensive regulatory review prior to approval. Researchers are looking for twenty subjects to undergo a one-time treatment; the children will be monitored for leukemia for fifteen years following the initial gene therapy.

Though it is a rare disease, SCID entered the cultural consciousness in the 1970’s and 80’s through extensive media coverage of David Vetter, dubbed “the boy in the plastic bubble.” Vetter died in 1984 following an unmatched bone marrow transplant from his sister, a transplant which inadvertently infected David with the Epstein-Barr virus.

The Consortium is an international collaboration that includes researchers from Children’s Hospital Boston, Hannover Medical School (Germany), and Institute of Child Health (London). Information on subject recruitment can be found here.

linkback url: http://singularityhub.com/2010/07/22/new-gene-therapy-trials-to-test-cure-for-bubble-boy-syndrome/

Gene Therapy Shows Promise With ‘Bubble Boy’ Disease

July 22, 2010

Gene Therapy Shows Promise With ‘Bubble Boy’ Disease

Researchers report some success 10 years after treatment, although some patients developed cancer

By Amanda Gardner
HealthDay Reporter

WEDNESDAY, July 21 (HealthDay News) — Eight of nine male infants born with so-called “Bubble Boy” disease were still alive and well nine years after they underwent gene therapy, French researchers report.
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Up to 11 years after the therapy, most patients had normal T-cell levels and were able to lead normal lives, including attending regular schools. Their weight and height were not stunted, as is usually the case with this condition.

But the gains did not come without a price. Almost half of the participants in the study developed acute leukemia after the therapy. Three survived, while one died.

Still, said William J. Bowers, an associate professor of neurology at the University of Rochester Medical Center in New York, “this is a very substantial advance.”

And, he added, since these procedures were performed (between 1999 and 2002), additional advances have been made in terms of the virus vectors used to insert the corrected genes which, once tested in patients, could reduce the risk of cancer.

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

“Bubble Boy” disease, known as X-linked severe combined immunodeficiency (SCID-X1), occurs in at least one in every 50,000 to 100,000 newborns, according to the National Institutes of Health.

It’s caused by mutations in the IL2RG gene, which interferes with the normal production of immune system cells known as lymphocytes.

Boys with the condition — only boys inherit the gene — have no T-cells and so are unable to fight off infections.

The first treatment of choice for these patients is a bone marrow or cord blood transplant, but that requires a matched donor and can involve serious complications.

The nine boys in this study — who had a median age of 7 months at the time they received the corrected gene — were not eligible for transplants because no good matches were available.

Researchers removed CD34+ cells, a type of stem cell found in the bone marrow, added a corrected gene, then reinserted them into the respective patients, all of whom were placed in isolation.

The patients were able to leave the isolation unit 45 to 90 days after the procedure, and none developed any severe infections, although all did get Varicella zoster virus (which causes chicken pox). The infection wasn’t severe enough to require hospitalization.

Some of the patients also had chronic rhinitis (runny nose) and two patients developed warts, though these subsequently went away.

The most serious side effect was the development of T-cell acute lymphoblastic leukemia in three patients, one of whom died. The other three successfully underwent chemotherapy.

Participants all had healthy T-cells up to 11 years after the initial therapy.

“I think the field of gene therapy is starting to see clinical successes and is going to go forward fairly rapidly,” Bowers said.

The study appears in the July 22 issue of the New England Journal of Medicine.

More information

Visit the National Library of Medicine for more on this condition.

linkback url: http://health.usnews.com/health-news/family-health/cancer/articles/2010/07/21/gene-therapy-shows-promise-with-bubble-boy-disease.html

Study Shows Hope for Gene Therapy

July 7, 2010

Study Shows Hope for Gene Therapy

Researchers have launched a new gene-therapy trial for children with a rare disease known as “bubble boy syndrome,” reflecting fresh hopes that the strategy of delivering working genes can be used to treat many intractable ailments.

In the new study, sponsored in the U.S. by investigators at Children’s Hospital Boston and expected to open at five sites around the world, scientists plan to enroll 20 boys with SCID-X1, which stands for severe combined immunodeficiency, X-linked—a genetic condition that affects boys and leaves them unable to fight germs. Without treatment, which is currently possible only by bone-marrow transplantation, most children die before age one.

The study comes seven years after two similar trials in Europe—one in Paris and one in London, involving a total of 20 children—were temporarily halted when two participants were diagnosed with leukemia. Three others eventually developed the blood cancer, and one died. Those who survived were cured of SCID-X1, but the episode prompted the U.S. Food and Drug Administration to put a hold on certain gene-therapy studies.

While gene-therapy studies in other diseases have gone forward, the new trial is the first involving SCID-X1 to take place in the U.S. since the hold. Researchers believe they have stripped out the feature of the treatment that caused leukemia.

“If the trial is successful, we think what we are doing can apply to other rare diseases as well,” said David Williams, chief of hematology/oncology at Children’s Hospital Boston and lead investigator for the U.S. sites.

In gene therapy, scientists try to correct a problem caused by a defective or non-functioning gene. A normal gene is delivered via what scientists call a vector, typically a virus genetically altered to contain human DNA. The idea is that this normal gene will begin producing a protein that has been missing or not working and cure the disease.

The earlier SCID-X1 trials, along with the death in 1999 of 18-year-old Jesse Gelsinger four days after starting gene therapy at the University of Pennsylvania for a different genetic condition, intensified regulatory scrutiny and dampened enthusiasm for the new technology. Some scientists began to wonder whether gene therapy was too risky and too complex to become a safe and effective treatment.

But recent findings from several studies are rekindling excitement for the approach. Last fall, a team led by researchers at Children’s Hospital of Philadelphia and University of Pennsylvania School of Medicine reported they had successfully injected a gene via a genetically engineered vector into the retinas of 12 patients suffering from a blindness-causing genetic disease called Leber’s congenital amaurosis. All patients had some improvement in eyesight.

In another report last year, European researchers said they successfully delivered a gene into the blood cells of two patients with a rare, fatal brain disease called X-linked adrenoleukodystrophy (ALD). Patrick Aubourg, professor of pediatrics at University Paris Descartes, said the treatment halted progression of the disease. Three years later, the patients remain stable and can attend school.

The preliminary findings helped Genetix Pharmaceuticals Inc., of Cambridge, Mass., raise $35 million in venture capital to finance additional research, said Nick Leschly, the company’s interim president.

The data in these and other reports involve small numbers of patients, but “we’re seeing the first evidence of real therapeutic efficacy,” said Susan Robinson, chief executive officer of Seattle-based Targeted Genetics Corp., which is involved in an ongoing gene-therapy trial in Britain for Leber’s congenital amaurosis.

In the new SCID-X1 trial—which is open in London and Boston and undergoing regulatory review in Los Angeles, Cincinnati and Paris—researchers will take stem cells from a patient’s own bone marrow, deliver a functioning gene into those cells in the lab and then infuse them back into the patient. If all goes well, the cells will start producing a protein that will multiply and provide a functioning immune system.

Currently, SCID-X1 is treatable only by bone-marrow transplantation, preferably from a sibling who is an exact bone-marrow match. When successful, that halts progression of the disease. But patients who must resort to marrow from unmatched donors require chemotherapy and face other serious complications.

So gene therapy, if successful, could not only avoid the need for chemotherapy but correct the genetic defect in one treatment. “The possibility of curing a disease possibly forever after only one treatment is really amazing,” says Dr. Williams of Children’s Hospital Boston.

Dr. Williams wasn’t involved in the original trial, but helped found the Transatlantic Gene Therapy Consortium seven years ago to set a new course for SCID-X1 trials following the leukemia problems. The group—including researchers from the UCL Institute of Child Health in London, Necker Hospital in Paris and Hannover Medical School in Germany—has vetted data, devised new laboratory experiments and redesigned the vehicle delivering the normal gene.

As part of the redesign, the parts of the vector thought to have activated leukemia-causing genes have been taken out. The researchers successfully tested the new vector in animals and in lab studies and believe the problem has been eliminated, says Luigi Notarangelo, the site investigator for the trial at Children’s Hospital Boston. Study participants will be monitored for 15 years to rule out any cancer risk.

The disease is very rare—fewer than one in 200,000 babies are born with the X-linked version of SCID each year—so the consortium adopted a common protocol to try to enroll patients more quickly.

Meantime, St. Jude Children’s Research Hospital, Memphis, Tenn., is planning a separate gene-therapy trial for infants with SCID-X1. The St. Jude’s researchers developed their own viral vector they say will lower the risk of leukemia. The investigators are hoping to begin enrollment in late 2010 or early 2011, a spokeswoman said.

linkback url: http://online.wsj.com/article/SB10001424052748704178004575351012766954840.html

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