The Second Coming of Gene Therapy

The Second Coming of Gene Therapy
09.02.2009
For years, gene therapy produced tons of hype but no results. Recently, though, new approaches have yielded its first successes: breakthrough treatments for blindness, cancer, and the deadly bubble boy disease.
by Jill Neimark

“For the first two years of her life, my daughter, Katlyn, was knocking on heaven’s door every day,” says Daisy Demerchant, a 26-year-old mom living in Centreville, New Brunswick, just north of Maine. “Two months after she was born she started getting sick, and she never got better.” At six months Katlyn was diagnosed with “bubble boy” disease, formally known as severe combined immunodeficiency (SCID), which robs the immune system of the ability to fight infection. There are many causes of this disorder; in Katlyn’s case it was lack of the enzyme adeno­sine deaminase, or ADA, which rids the body of a natural toxin called deoxyadenosine. When the toxin builds up, it destroys T and B lymphocytes, the body’s infection-fighting immune cells. As a result, Katlyn’s immune cells were dying.

Treatment options ranged from risky to grim. One was a bone marrow transplant, in which imported donor cells could manufacture healthy T cells to fight invading germs. But bone marrow transplants can have lethal complications and often require drugs that further inhibit the patient’s immune system, leaving a window of vulnerability until the transplant kicks in. Another potential treatment involved injections of the ADA enzyme itself. But there was a risk Katlyn would develop antibodies to the drug, rendering it useless. Without any treatment at all, she would simply die.

While weighing their options, doctors put the little girl on protective antimicrobials and sent her to a hospital eight hours from her home. She became another fragile bubble baby sequestered from the world. “My husband quit his job building fire trucks, and we lived with Katlyn in the hospital for 15 months,” Demerchant says. The parents had to wear sterile gowns, booties, masks, and gloves, and the urge to touch their child—let alone hug and kiss her—had to be put on hold.

Just when it seemed as if Katlyn’s life might never improve, science and fate intervened. Her specific condition, called ADA-SCID, had long tantalized researchers seeking to repair genetic defects with a technique called gene therapy. Rare, deadly, and caused by a single gene mutation, it was a perfect proof-of-principle condition for anyone seeking to replace damaged DNA with genes that did the job. With all her troubles, little Katlyn Demerchant had been almost made to order for Fabio Candotti, a senior investigator at the National Human Genome Research Institute at the National Institutes of Health in Bethesda, Maryland.

Before Katlyn showed up at NIH, the doctors there were already well prepared: They had inserted healthy human ADA genes into a modified mouse retrovirus—a type of virus that can enter human cells and transfer new genetic material right into the DNA strands in their nuclei.

Once Katlyn arrived in May 2007, Candotti and his team removed stem cells from her bone marrow and exposed them to the engineered retrovirus, creating a human-virus hybrid. Then they injected the hybrid cells back into Katlyn. Like heat-seeking missiles, the retooled stem cells automatically found their way back home to the marrow. There, they began to specialize, creating all of the secondary or “daughter” cells that such stem cells normally produce—including healthy T cells with functioning ADA genes.

Everybody waited while Katlyn, still stuck inside the bubble, learned to walk on the floor of her sterile isolation room and to play through the protective window with a visiting dog named Toffee. On September 3, blood tests showed Katlyn’s immune system was being populated with robust, functioning T cells. She was so restored, in fact, that her parents were able to take her outside for the first time since she was an infant. “The first day we took her out she was really quiet and a little terrified,” Daisy Demerchant says. “The second time she started running around and asking us a million questions. She’d point to the sun, clouds, leaves, cars, everything imaginable, and ask us what it was. Ever since that day, she has never wanted to stay inside.”

Six months after her gene therapy transplant, Katlyn was so healthy that doctors let her return home to Canada. It can take a year or longer for the immune system to reconstitute itself in full, so Katlyn still takes antimicrobials as a precaution, but today she plays outside, even in the dirt, and is resistant enough to fly on a commercial plane.

The new DNA treatments for Katlyn Demerchant and other bubble babies are nothing short of remarkable, the culmination of a major push to perfect gene therapy for the disease, Candotti says. Across the ocean, in Italy, bubble babies with ADA-SCID are also being cured: A trial led by Alessandro Aiuti, a molecular biologist at San Raffaele Telethon Institute for Gene Therapy in Milan, restored the immune system in eight of ten children, while a ninth had significant improvement.

And bubble babies are far from alone. In Europe and the United States, gene therapists have restored vision in individuals suffering from a rare genetic disorder that inevitably leads to blindness. In Texas, a team has manipulated genes in order to put deadly cancers into complete remission. Building on these successes, gene therapy may soon be used to correct hereditary genetic diseases like cystic fibrosis, hemophilia, and Tay-Sachs and to activate the immune response against a wide variety of infectious diseases and cancers. Gene therapy and its adjuncts may help us trick the body into growing new tissue to rejuvenate arthritic joints, fix injured hearts, and speed the healing of wounds….Continued

link url: http://discovermagazine.com/2009/sep/02-second-coming-of-gene-therapy

Analysis: Gene therapy has immense potential

After almost two decades, gene therapies have recently started to deliver on their immense promise

Mark Henderson, Science Editor

Gene therapies have been a part of medicine for almost two decades. Only recently have they started to deliver on their immense promise after a string of setbacks raised doubts about the safety of manipulating human DNA, centre, to treat disease.

The idea behind gene therapy is that by inserting new copies of a particular gene into human cells, it should be possible to correct defects, or to enhance beneficial biological processes. This can be done with viruses, which introduce their own genetic material into the cells they infect, and can be engineered to carry a human gene.

This technique was first performed successfully in 1990, when an American team used it to treat Ashanti de Silva, a four-year-old girl with severe combined immune deficiency (SCID). This genetic disease leaves children without a functioning immune system — it is known as “bubble baby” syndrome because sufferers must often be shielded from germs in a sterile pouch. The technology, however, has since encountered several problems. In 1999 Jesse Gelsinger, an 18-year-old with an inherited liver disease who had volunteered for a gene therapy trial, died after suffering a massive immune reaction to the viral vector. Further safety fears were then raised when five children in an Anglo-French trial of a SCID gene therapy developed leukaemia because the viral vector interfered with a gene that can trigger cancer.

Gene therapy has also failed, so far, in the treatment of diseases such as cystic fibrosis: these affect so many of the body’s tissues that it is difficult to infect all the cells that need to be corrected. And there are ethical concerns about using gene therapy to modify cells permanently, especially if these changes can be passed on to subsequent generations..

New viral vectors, however, have lowered the risk of immune reactions and inadvertent activation of cancer genes. Many of these also work only for a short period of time, so any damaging effects should be reversible.

Several trials have also started to produce extremely encouraging results. The Anglo-French SCID therapy, which now uses a new vector, seems to be capable of curing the disease indefinitely. Another UCL team, led by Robin Ali, has improved the sight of patients with Leber’s congenital amaurosis, a genetic cause of blindness. Cerepro, an Ark Therapeutics drug that uses the same vector as the foetal growth promoter, has had good results against brain cancer.

What links these success stories is that they involve diseases that affect a particular type of tissue, such as white blood cells or retinal cells, which are relatively simple to target for infection with a modified virus. Severe foetal growth restriction falls into the same category: it should only be necessary to influence the uterine arteries to get a result.

The dream of using gene therapy to treat more systemic diseases such as cystic fibrosis, muscular dystrophy or spinal muscular atrophy, however, remains more distant. The challenge of conveying the replacement gene to cells throughout the body is one that still has to be overcome.

• Mark Henderson’s 50 Genetics Ideas You Really Need to Know. Quercus £9.99. To buy it for £9.49 inc p&p call 0845 2712134 or visit timesonline.co.uk/booksfirst

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ANALYSIS-Gene therapy edges towards commercial reality

Reuters
ANALYSIS-Gene therapy edges towards commercial reality
02.27.09, 5:46 AM ET

United Kingdom –

* Gene therapy advances after troubled history

* Ark’s Cerepro may be first gene medicine in Europe or U.S.

* More than 1,470 gene therapy trials since 1989

By Ben Hirschler, European Pharmaceuticals Correspondent

LONDON, Feb 27 (Reuters) – Gene therapy may be about to become a commercial reality, 20 years after the first experiments with the ground-breaking medical technology.

But the tale of two biotech companies — one British and one U.S. — suggests a tricky road ahead.

On the one side, French authorities last week allowed an experimental gene medicine from Britain’s Ark Therapeutics to be prescribed to certain patients with brain cancer, even though it is not approved for general use.

The news boosted hopes that the European Medicines Agency will clear Ark’s drug Cerepro for sale across the European Union in the second half of 2009.

By contrast, U.S.-based Introgen Therapeutics — which had been competing to get the first gene therapy approved in Western markets — filed for bankruptcy in December, after a regulatory setback for its experimental cancer drug Advexin.

The last two decades have seen more than 1,470 clinical trials involving gene therapy, two-thirds of them aimed at cancer, according to the Journal of Gene Medicine.

But the only drug to get to market so far has been one for for head and neck cancer from Shenzhen SiBiono GeneTech, which was approved in China in 2003 on data that most analysts do not believe would have supported a Western green light.

Some of the other U.S. and European companies in the space include Genzyme, Targeted Genetics, GenVec, Neurologix, Amsterdam Molecular Therapeutics and Oxford BioMedica.

BUBBLE BOY DISEASE

The idea of using genes to treat disease gained credibility in 1990, when the world’s first clinical tests showed early success against a rare condition caused by faulty genes, called severe combined immunodeficiency (SCID).

People with SCID — also known as “bubble boy disease” — cannot cope with infections and usually die in childhood.

The field then suffered a major setback when an Arizona teenager died in a gene therapy experiment in 1999 gene and two French boys with SCID developed leukaemia in 2002.

More recently, though, doctors have made encouraging advances.

Last year, two separate academic teams reported success in using gene therapy for a type of inherited blindness call Leber congenital amaurosis.

And last month an extended follow-up study of SCID children concluded that eight of 10 treated seemed to have been cured, leading the New England Journal of Medicine to declare that gene therapy was “fulfilling its promise”.

“There have been setbacks but we are finally making progress,” Thierry VandenDriessche, president of the European Society of Gene and Cell Therapy, told Reuters.

“The tools to deliver genes into cells have been perfected and have become safer and more efficient and we are starting to see the fruits of this in the clinic.”

NEW BRANCH OF MEDICINE

Nigel Parker, chief executive of Ark, believes his company is ahead in what will become a major new branch of medicine. He plays down past setbacks as inevitable learning points for any new technology.

“If you think how long it takes for a new therapeutic idea to come to market, it does take about 20 years. So this is not too far away from the normal pharmaceutical cycle,” he said.

Industry analysts are still divided as to how commercially successful Cerepro and other gene-based medicines will be.

“We’re definitely closer but we are still not quite there yet,” said Nomura Code analyst Samir Devani, who forecasts peak worldwide sales for Cerepro of $250 million a year.

Paul Cuddon of KBC is more sceptical about the drug’s prospects, pending the release of full Phase III trial data.

One of the big hurdles for gene therapy has always been how to get therapeutic genes to the right part of the body.

Normally, a virus is used as a carrier. But viruses can trigger serious immune reactions and damaging genetic mutations, if they integrate into the wrong part of the genome. They are also difficult to steer, making it hard to ensure that genes get to the right places in the body. One option is to adopt a more localised approach.

In the case of blindness, a common cold virus is used to deliver a corrective gene directly into the eyes of patients.

Cerepro, meanwhile, works via injections into the brain that transmit a gene for making a protein, which then reacts with an antiviral drug to produce a chemical that kills cancer cells. That makes Ark’s drug a temporary and local treatment.

“If Cerepro gets approved fully for European use, I don’t think that changes the risk profile for any other gene therapy because these products are so specific,” said Piper Jaffray analyst Sam Fazeli. (Editing by David Holmes)

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Italian professor makes scientific breakthrough

Dr. Alessandro Aiuti introduces new gene therapy to treat “bubble” syndrome

By Mariella Policheni

Forced to live within the confines of the home, unable to have contact with the outside world or to live a normal life like other children – those afflicted by Severe Combined Immunodeficiency Disease (ADA-SCID) can finally smile.
The treatment administered by the team guided by professors Alessandro Aiuti and Maria Grazia Roncarolo at the Istituto San Raffaele, has been proven to be effective: the final results of the experimentation that began in 2000 were published in the New England Journal of Medicine.
It is a therapy that has changed the lives of many “bubble babies” – so called because they are forced to live in a sterile environment – who are now finally free to go out, whether it’s to school, or to play with friends. They are now able to lead a much more normal life.
Professor Aiuti is a medical researcher who boasts a brilliant scientific career. After acquiring his degree in medicine and surgery at the Università di Roma La Sapienza, and completing his doctorate in Human Molecular and Cellular Biology research at the same university, he went on to specialize in Haematology at the Università degli Studi di Milano. From 1994 to 1996, he did research at the Genetics Department at Harvard Medical School in Boston, and is currently associate professor of Pediatrics at the Univesità degli studi di Roma Tor Vergata. He has also published 63 scientific works in international magazines.

The stem cell gene therapy being used by your team has proven to be successful. How many children have you treated?

“Since 2000, we’ve successfully treated 12 children who came from all over the world. Among them was Parker, a Canadian child.”

We’ve been following Parker DesLauriers’ story. What can you tell us about this case?

“A year and a half has passed since Parker underwent treatment. The results are good. Parker is recovering and his immune system is returning to normal function, so we are satisfied with his response to the therapy.”

Will Parker have to return to Milan for a checkup?

“Parker is a child who is growing nicely, and will return to Milan two years after the therapy.”

How did you apply the technique?

“We remedied the defect in the stem cells by taking bone marrow from children and then transplanting back their own marrow. By doing this, the cells made their way back to the bone marrow where they began producing blood cells including lymphoid cells – the cells that protect us from infections but that have been missing in these children since birth.”

Can gene therapy involving stem cells treat other illnesses? What are your goals for the future?

“Goals for the future are to expand the use of stem cells to the Wiskott-Aldrich Syndrome, another form of immunodeficiency, and to Metachromatic Leukodystrophy, a degenerative nervous system condition.”

This Italian research demonstrates the excellent preparedness of Italian scientists. You live and work in Italy, but many other researchers have leftthe country. Is it difficult to work in Italy? Why did you stay?

“I returned after two years in Boston, because I believed in the value of Italian research. We have many excellent scientists. It is possible, by carrying out high-quality research, to obtain results – for us, this was made possible thanks to the Fondazione Telethon. Unfortunately, government funding during recent years is still not enough to draw researchers back to Italy. It’s very important to have more investment in research. Good quality work can be achieved in Italy, and this example shows that we need to have more faith in research.”

Your work is very difficult with a high degree of commitment but also a lot of satisfaction. How do you feelabout being able to save the lives of the many children who come to Milan each year from all over the world?

“I am a doctor above all, so seeing tangible results from many years of laboratory research is great satisfaction – especially seeing children grow up to be healthy, and to see them playing. For me, it’s like having many offspring scattered throughout the world – it’s the source of great joy.”

Publication Date: 2009-02-22
Story Location: http://www.tandemnews.com/viewstory.php?storyid=8935

Gene therapy cures ‘bubble boy disease’

NEW YORK — Gene therapy seems to have cured eight of 10 children who had potentially fatal “bubble boy disease,” according to a study that followed their progress for about four years after treatment. The eight patients were no longer on medication for the rare disease, which cripples the body’s defenses against infection. The successful treatment is reported in Thursday’s issue of the New England Journal of Medicine and offers hope for treating other diseases with a gene therapy approach.

Bubble boy disease is formally called severe combined immunodeficiency, or SCID. This genetic disorder is diagnosed in about 40 to 100 babies each year in the United States. The nickname comes from the experience of a Houston boy, David Vetter, who became famous for living behind plastic barriers to protect him from germs. He died in 1984 at age 12.

He had the most common form of SCID. Recent studies found that gene therapy produced impressive results for that form of the disease, but also carried a risk of leukemia.

The new study involved a different, less common form of SCID – and one that holds a key position in medical history. In 1990 it became the first illness to be treated by gene therapy, according to the U.S. government. Two Ohio girls improved but continued to take medication.

This form of SCID arises in babies with a genetic defect that leaves them deficient of an enzyme called adenosine deaminase.

Patients can be treated with twice-weekly shots of the enzyme or a bone marrow transplant, but the medicine is expensive and marrow transplants don’t always work.

Gene therapy for the new study was performed in Italy and Israel. Researchers removed marrow cells from the patients, equipped the cells with working copies of the gene for the enzyme, and injected the cells back into the patients. In most cases, that was done before age 2.

The journal article reports the outcome two to eight years later, with an average of four years. All 10 patients were still alive, but two needed further treatment. None showed signs of leukemia or other health problems from the therapy, the researchers said.

Dr. Donald Kohn, a SCID expert at Childrens Hospital Los Angeles and the University of Southern California, said scientists are trying to understand why gene therapy produces a leukemia risk with the most common form of SCID but not the enzyme-related form.

The new findings are good news for the idea of using gene therapy to treat some other blood cell disorders, including sickle cell disease, said Kohn, who didn’t participate in the new study.

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6631182&rss=rss-wabc-article-6631182

New gene therapy could help Lehi’s ‘bubble girl’

Tuesday, 03 February 2009

Ace Stryker – Daily Herald

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A Lehi mother says she’s looking into experimental gene therapy to help her 7-year-old daughter, who was born with “bubble boy disease,” after European scientists cured eight of 10 children using the method.

Emily Heaps was born with severe combined immunodeficiency, a genetic defect that robs the body of its natural immune system. Contrary to popular belief, Emily doesn’t live in a bubble; her world is kept clean using equal portions Lysol and diligence. But since a bone marrow transplant last August, she’s been mostly isolated at home as her system recovers. It will be eight months before the family has a good idea of whether her body will accept the transplant, said her mother, Jill.

“She could start rejecting any time,” she said, noting that Emily should be able to return to school and church when the wait-and-see period is up.

But if the transplant doesn’t take, Jill said the family is encouraged by the results of gene therapy coming out of Europe. She said Emily’s doctors are looking into the test cases and could pursue something similar if necessary.

“That’s definitely an option if this transplant doesn’t work,” she said. “The first option is always the bone marrow transplant if you can have a match.”

There are concerns with the gene therapy route, Jill said: Some patients have developed leukemia as a result. But faced with the decision between that and no treatment — which would inevitably be fatal — it’s not a difficult choice, she said.

“When you get to the point where you don’t have a choice, you’re going to try anything you can,” she said. “If you have other choices, you always go for those first.”

The eight patients in Italy and Israel who were cured with the gene therapy are no longer on medication for the rare disease. The successful treatment was reported in last Thursday’s issue of the New England Journal of Medicine.

Severe combined immunodeficiency is diagnosed in about 40 to 100 babies each year in the United States. The nickname comes from the experience of a Houston boy, David Vetter, who became famous for living behind plastic barriers to protect him from germs. He died in 1984 at age 12.

Emily’s strain of SCID — a relatively rare one caused by a mutation in the gene that encodes a protein called adenosine deaminase — is one that holds a key position in medical history. In 1990 it became the first illness to be treated by gene therapy, according to the U.S. government. Two Ohio girls improved but continued to take medication.

In the test cases, researchers removed marrow cells from the patients, equipped the cells with working copies of the gene for the enzyme, and injected the cells back into the patients. In most cases, that was done before age 2.

Dr. Donald Kohn, a SCID expert at Childrens Hospital Los Angeles and the University of Southern California, said scientists are trying to understand why gene therapy produces a leukemia risk with the most common form of SCID but not the enzyme-related form.

The journal article reports the outcome two to eight years later, with an average of four years. All 10 patients were still alive, but two needed further treatment. None showed signs of leukemia or other health problems from the therapy, the researchers said.

• The Associated Press contributed to this report.
• Ace Stryker can be reached at 344-2556
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Gene Therapy for Immunodeficiency Due to Adenosine Deaminase Deficiency

Gene Therapy for Immunodeficiency Due to Adenosine Deaminase Deficiency

Alessandro Aiuti, M.D., Ph.D., Federica Cattaneo, M.D., Stefania Galimberti, Ph.D., Ulrike Benninghoff, M.D., Barbara Cassani, Ph.D., Luciano Callegaro, R.N., Samantha Scaramuzza, Ph.D., Grazia Andolfi, Massimiliano Mirolo, B.Sc., Immacolata Brigida, B.Sc., Antonella Tabucchi, Ph.D., Filippo Carlucci, Ph.D., Martha Eibl, M.D., Memet Aker, M.D., Shimon Slavin, M.D., Hamoud Al-Mousa, M.D., Abdulaziz Al Ghonaium, M.D., Alina Ferster, M.D., Andrea Duppenthaler, M.D., Luigi Notarangelo, M.D., Uwe Wintergerst, M.D., Rebecca H. Buckley, M.D., Marco Bregni, M.D., Sarah Marktel, M.D., Maria Grazia Valsecchi, Ph.D., Paolo Rossi, M.D., Fabio Ciceri, M.D., Roberto Miniero, M.D., Claudio Bordignon, M.D., and Maria-Grazia Roncarolo, M.D.

ABSTRACT

Background We investigated the long-term outcome of gene therapy for severe combined immunodeficiency (SCID) due to the lack of adenosine deaminase (ADA), a fatal disorder of purine metabolism and immunodeficiency.

Methods We infused autologous CD34+ bone marrow cells transduced with a retroviral vector containing the ADA gene into 10 children with SCID due to ADA deficiency who lacked an HLA-identical sibling donor, after nonmyeloablative conditioning with busulfan. Enzyme-replacement therapy was not given after infusion of the cells.

Results All patients are alive after a median follow-up of 4.0 years (range, 1.8 to 8.0). Transduced hematopoietic stem cells have stably engrafted and differentiated into myeloid cells containing ADA (mean range at 1 year in bone marrow lineages, 3.5 to 8.9%) and lymphoid cells (mean range in peripheral blood, 52.4 to 88.0%). Eight patients do not require enzyme-replacement therapy, their blood cells continue to express ADA, and they have no signs of defective detoxification of purine metabolites. Nine patients had immune reconstitution with increases in T-cell counts (median count at 3 years, 1.07x10⁹ per liter) and normalization of T-cell function. In the five patients in whom intravenous immune globulin replacement was discontinued, antigen-specific antibody responses were elicited after exposure to vaccines or viral antigens. Effective protection against infections and improvement in physical development made a normal lifestyle possible. Serious adverse events included prolonged neutropenia (in two patients), hypertension (in one), central-venous-catheter–related infections (in two), Epstein–Barr virus reactivation (in one), and autoimmune hepatitis (in one).

Conclusions Gene therapy, combined with reduced-intensity conditioning, is a safe and effective treatment for SCID in patients with ADA deficiency. (ClinicalTrials.gov numbers, NCT00598481 [ClinicalTrials.gov] and NCT00599781 [ClinicalTrials.gov] .)

linkback url: http://content.nejm.org/cgi/content/short/360/5/447?rss=1&query=current

Gene Therapy Works for Rare Immune Disorder

By Todd Neale, Staff Writer, MedPage Today
Published: January 28, 2009
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston. Earn CME/CE credit
for reading medical news
MILAN, Italy, Jan. 28 — A form of the rare “bubble boy disease” responds to gene therapy, with no long-term safety concerns, researchers said.

Action Points
* Explain to interested patients that this study found that replacing a defective gene provided improvements in the immune systems of almost all of the children with severe combined immunodeficiency caused by lack of adenosine deaminase.

All 10 children who had severe combined immunodeficiency (SCID) caused by lack of adenosine deaminase were still alive a median of four years after the gene for the missing enzyme was replaced, Maria-Grazia Roncarolo, M.D., of the San Raffaele Telethon Institute for Gene Therapy here, and colleagues reported in the Jan. 29 issue of the New England Journal of Medicine.

None of the patients developed leukemia, which has been a serious side effect in previous gene therapy studies in patients with X-linked SCID.

“Gene therapy restored normal immune function in five patients and resulted in significant improvement in lymphocyte counts and functions in the other five patients, leading to protection from infectious complications,” the researchers said.

SCID due to a deficiency of adenosine deaminase is fatal if left untreated. In affected patients, the build-up of compounds the enzyme is meant to break down impairs the proliferation of lymphocytes, which leaves the patient vulnerable to infection.

It can be treated by a hematopoietic stem cell transplant from an HLA-identical sibling — the treatment of choice — or enzyme-replacement therapy, although both treatments have limitations, according to the researchers.

A transplant from a sibling is available for only a minority of patients and enzyme-replacement therapy often does not sustain the correction of the immunodeficiency, they said.

A promising avenue of research is the use of gene therapy, in which the missing gene is transferred by way of a retroviral vector into hematopoietic stem cells harvested from the patient’s bone marrow. The cells are then re-infused into the patient.

Dr. Roncarolo and colleagues tried this approach with 10 children (six girls and four boys) ranging in age from about seven months to 5.6 years. They first went through nonmyeloablative conditioning with the chemotherapeutic agent busulfan.

Four of the patients had undergone a failed bone marrow transplant from a mismatched related donor and six had had an inadequate response to enzyme-replacement therapy. One had been diagnosed at birth and had not yet undergone any treatments.

Nine of the patients had at least some degree of immune reconstitution with significant increases in T-cell counts at one year (P=0.004) and three years (P=0.03) and normalization of T-cell function, the researchers said.

At one year, 88% of T cells, 52.4% of B cells, and 59.2% of natural killer cells contained the previously deficient enzyme.

Through the end of follow-up ranging from 1.8 to 8.0 years, eight of the patients no longer needed enzyme-replacement therapy and did not show signs of defective detoxification of purine metabolites. The other two patients initiated replacement therapy after gene therapy, one at 4.8 months and one at 4.5 years.

Five patients had T-cell counts within the normal range and four had B-cell counts within normal range.

Five patients demonstrated antibody responses after exposure to vaccine or viral antigens.

In addition, the researchers said, “most patients had abnormalities in neuropsychomotor development at onset that improved during the follow-up period.”

“Effective protection against infections and improvement in physical development made a normal lifestyle possible,” the researchers said.

Serious adverse events included neutropenia lasting longer than 30 days in two patients, hypertension in one patient, central venous catheter-related infections in two patients, Epstein-Barr virus reactivation in one patient, and autoimmune hepatitis in one patient.

None of the patients developed leukemia, unlike the quarter of X-linked SCID patients who develop the malignancy after gene therapy.

Donald Kohn, M.D., of the University of Southern California and Children’s Hospital Los Angeles, and Fabio Candotti, M.D., of the National Human Genome Research Institute in Bethesda, Md., speculated in an accompanying editorial that this discrepancy “may reflect important biologic differences between the corrected hematopoietic stem cells in X-linked SCID and SCID due to adenosine deaminase deficiency.”

They pointed out that the protein coded by the gene responsible for X-linked SCID “provides a proliferation signal that may cooperate with the concomitantly deregulated expression of a proto-oncogene in proximity to the gene-transfer vector-integration site, favoring the establishment of malignant cells.”

Drs. Kohn and Candotti said that the outcomes of this and other gene therapy trials “are at least as good as, and arguably better than, the results reported for allogeneic transplantation,” and that studies should continue on gene therapy.

Similar and newer approaches may be used for the treatment of hemoglobinopathies, hemophilia, muscular dystrophy, congenital retinopathies, neurodegenerative disorders, and other genetic diseases, they said.

The study was supported by grants from the Italian Telethon Foundation, the Association Francaise contre les Myopathies-Telethon, the independent drug research program of the Italian Medicines Agency, and the European Commission.

One of Dr. Roncarolo’s co-authors, Claudio Bordignan, M.D., reported being the chief of the board and CEO of MolMed, which manufactured the vector and engineered cells used in the study. He left the study when he became CEO.

The editorialists reported no conflicts of interest.

Primary source: New England Journal of Medicine
Source reference:
Aiuti A, et al “Gene therapy for immunodeficiency due to adenosine deaminase deficiency” N Engl J Med 2009; 360: 447-458.

Additional source: New England Journal of Medicine
Source reference:
Kohn D, Candotti F “Gene therapy fulfilling its promise” N Engl J Med 2009; 360: 518-521.

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