Treatment for Growth Failure in Patients With X-Linked Severe Combined Immunodeficiency: Phase 2 Study of Insulin-Like Growth Factor-1

January 10, 2012


This study will evaluate the safety and effectiveness of insulin-like growth factor-1 (IGF-1) to treat patients with X-linked severe combined immunodeficiency (XSCID). Those who have XSCID lack white blood cells that protect their bodies from invasion by all types of germs. IGF-1 is the main hormone responsible for the body’s growth and metabolism. As a medication, IGF-1 is Increlex[(Trademark)] (mecasermin),

Patients ages 2 to 20 who have not yet begun puberty, have a diagnosis of XSCID, and are shorter than the 3rd percentile for their age may be eligible for this study. This study will last about 3 years, and patients’ visits will be scheduled at 3-month intervals. Patients will have a physical history and exam, X-rays, electrocardiogram, blood tests, and body measurements.

Patients will take estradiol orally for 2 days, to help avoid false results of growth hormone (GH) levels in blood samples. Then provocation testing is done, with two tests back to back. It determines blood levels of GH and the body’s response to testing with drugs called arginine and clonidine. Patients are admitted to the pediatric inpatient unit and will have an intravenous (IV) line placed in the arm. Arginine is given by IV over 30 minutes, and blood samples are taken. Right after arginine testing, the clonidine tablet is given. The IGF-1 generation test is then done to see if the body makes IGF-1 as a product in response to injections of GH for 5 consecutive days. This test does not require that patients are inpatients, but after Day 8, patients must be admitted to the pediatric unit to have blood sampling, start Increlex injections, and start close monitoring of blood sugar levels. They will learn how to do a self-injection and follow other advice. They will complete records about the injection site, symptoms, and side effects-keeping records for at least the first 2 days after going home, with each dose change, and as needed. Patients stick their fingertip and place a small drop of blood on a blood sugar monitoring strip. The strip is put into a glucometer-a small hand-held device to measure the blood sugar level. Patients will be instructed to always have a source of sugar available in case blood sugar is too low.

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Pioneering surgery gives Lincolnshire seven-year-old ‘new lease of life’

July 15, 2011

Pioneering surgery gives Lincolnshire seven-year-old ‘new lease of life’


WITH a cheeky smile and bucket-loads of energy, little Toby Booth seems like any other child as he plays at home.

But the 7-year-old has more reason than most to be cheerful following life-changing surgery for a condition that affects only a handful of children in the world.


Toby suffers from Severe Combined Immunodeficiency (SCID), which puts him at risk of life-threatening complications, including organ damage.

His condition is so complex that he has to be monitored by a team of specialist medics at The Children’s Hospital in Sheffield on a weekly basis.

And after his illness caused problems with his gallbladder, doctors carried out surgery to remove it.

Mum Helen Booth, 46, of Saxilby, says the pioneering keyhole surgery, coupled with drug infusions to help him fight infections, have given her son a “new lease of life”.

“With Toby’s condition, it has literally been like the film, Boy In The Bubble,” said Mrs Booth, a full-time mum and carer for Toby.

“Now, he goes to school and lives the life of a normal little boy. We went down to Poole and he went on to the beach and swimming – things that he had never been able to do before.

“This is what we’ve been fighting for, for Toby to have a normal life. You can’t have him go through all of this and then tell him that he can’t live a regular life.

“He’s the most cheerful and happy little boy and he never feels sorry for himself.”

Toby was diagnosed with the genetic condition aged two and has already overcome a series of life-threatening complications.

When he was just 3 years old, he had his spleen removed and a bone marrow transplant.

The recent operation at The Children’s Hospital by consultant paediatric surgeon Sean Marven, is hoped to help prevent further complications.

“Toby made a remarkably fast recovery after his surgery. He was up and about the next morning,” said Mrs Booth.

“We’ve been with the hospital for many years and have always been impressed with the care Toby has received from the whole team.

“He’s a very resilient character and we’re very proud of the way he copes with his condition.”

Mr Marven said: “The advantage of keyhole surgery is that the patient has just a couple of small incisions in their abdomen so they recover far more quickly than if they’d had traditional surgery.

“The next morning, Toby was out of bed and running around. We’ve only done a couple of gallbladder operations like this so far and they’ve all been highly successful.

“We like to be able to offer our patients the fastest and most reliable operations which get them back on their feet fast and have fewer risks.”

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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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NIH funds Center of Excellence for Molecular Hematology at Cincinnati Children’s

October 7, 2010

NIH funds Center of Excellence for Molecular Hematology at Cincinnati Children’s

CINCINNATI – Cincinnati Children’s Hospital Medical Center has been named one of five national Centers of Excellence for Molecular Hematology to find new gene and cell therapies for inherited diseases affecting blood cells.

The National Institute of Diabetes, Digestive and Kidney Diseases, one of 19 National Institutes of Health, has approved a five-year, $3.4 million grant for Cincinnati Children’s to establish the multi-disciplinary center. The center blends Cincinnati Children’s extensive research and clinical expertise, including its close collaboration with research affiliate, the University of Cincinnati College of Medicine.

A key aim of the Cincinnati Center for Molecular Hematology is to accelerate the discovery of new therapeutic approaches for conditions like sickle cell anemia, thalessemia, leukemia, immunological disorders and other blood cell-based diseases, according to Yi Zheng, Ph.D., director of Experimental Hematology and Cancer Biology and director of the new center. The center will also help speed the transition of new therapies from the research laboratory to clinical trials.

“We have a strong basic research pipeline at Cincinnati Children’s and the ability to rapidly translate basic research into the clinic,” Dr. Zheng said. “The medical center is one of the few institutions in the country that can claim excellence in basic science, expertise in genetic manipulation under Good Manufacturing Practice conditions, and also provide outstanding cell and gene therapies and patient care at a single location.”

The challenge is to understand and correct diseases caused by interactions between mutated genes and environmental factors that adversely affect blood cells. Researchers believe that successfully applying molecular and cell therapeutics to blood cells that can be transplanted into patients will provide life-long cures for inherited diseases.

Cincinnati Children’s is already working on gene therapy trials for new treatments of sickle cell anemia, X-SCID (X-linked severe combined immunodeficiency), solid cancers such as rhabdomyosarcoma and Ewing’s sarcoma, and a number of other diseases.

The NIDDK grant helps fund four research cores that support the research activities of multiple investigators. The cores are vital to the rapid and efficient translation of original discoveries from the laboratory to the clinic, Dr. Zheng said

The research cores supported by the grant are:

* The Translational Core. The core includes 10,000-square-feet of tightly controlled “clean room” laboratory space. The facility can manipulate human cells outside of the body to create cell products for therapeutic use in specific diseases. It also produces viral vectors to allow the delivery of specific genetic information for treating disease
* The Genomics and Genetics Core. The core provides leading edge genomic analysis of blood cell diseases and determining the normal genetic traits of blood stem and progenitor (early stage) cells.
* The Mouse Xenotransplant/Transgenic Core. The core maintains specialized mouse strains and provides mouse transplant and transgenic services that allow scientists to study mouse models of human disease.
* The Flow Cytometry Core. This laboratory allows scientists to analyze and sort different types of blood cells.

The center designation comes after years of basic science discoveries in genetics and genomics have put researchers on the threshold of exciting new therapeutic approaches for blood cell disorders, according to Arnold Strauss, M.D., director of the Cincinnati Children’s Research Foundation, chief medical director of the medical center, and chair of pediatrics at the UC College of Medicine.

“We are on the verge of being able to use novel interventions to treat and really cure disorders, such as sickle cell anemia, that severely impair normal lives for children and adolescents and cause premature death in young adults,” Dr. Strauss said. “After 40 years of watching afflicted children suffer and die, I am incredibly excited that the time is arriving for their cure.”

Helping secure the center of excellence designation is a decade of rapid growth in Cincinnati Children’s research activities and in its reputation. The medical center is the nation’s second largest pediatric research organization as measured by NIH funding, which totaled over $115 million in fiscal 2009 – an increase from $12.3 million just a decade ago. The medical center currently has 950,000 square feet of research laboratory space, with plans underway for an additional 300,000 square feet.

The expansion has included establishment of nearly two dozen research cores, with capabilities ranging from creating and maintaining stem cell lines to one of the largest academic bioinformatics and computing centers in the nation.

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Cannabis is firm’s ‘gateway drug’

August 2, 2010

Cannabis is firm’s ‘gateway drug’

Medical pot Has also designed a plant to produce a therapeutic enzyme

Postmedia News August 2, 2010

A reputation of any kind, even for a business, is hard to shake.

And when your company is the only federally licensed medical marijuana producer in Canada, that’s the first thing people think of when they hear the company’s name, says Brent Zettl, Prairie Plant Systems Inc.’s president and CEO.

But providing cannabis to patients authorized by Health Canada isn’t the Saskatoonbased company’s only focus, even if sales of the CanniMed herbal treatment account for between 60 and 65 per cent of its revenue, Zettl says.

“It’s kind of like our gateway drug, if I can use that term,” he says in an interview. “It’s our gateway drug to these other compounds that we’re planning to have produced in plants.”

For nearly 10 years, PPS has produced medical marijuana on a contract basis for the federal government. Originally grown in the deep depths of a decommissioned mine in Flin Flon, Man. -known unofficially as the Ganja Mine -PPS moved its hydroponic operation out of the town on the Saskatchewan border when the contract with the mine’s owner ended last summer.

PPS is still growing the marijuana for the government, but the location of the operation must remain confidential under federal regulations,

Casandra Kyle

Zettl says.

“North of the 49th and in between the Atlantic and the Pacific and Arctic oceans, that’s where it is,” he says.

Although the high-profile, legal and still-controversial practice of growing medical marijuana is what PPS is best known for, Zettl hopes the distinction will change over time.

“I think a lot of people forget this is a contract we bid on,” he says. “But we had a bigger purpose in mind. … Although it’s our reputation at this point, we’re trying to change that.”

The company, along with the Plant Biotechnology Institute, has designed a plant to produce a therapeutic enzyme known as adenosine deaminase, or ADA. The enzyme, Zettl explains, is part of the body’s immune system and is deficient in people with severe combined immunodeficiency disease, a condition often referred to as bubble-boy syndrome.

People with the disease must undergo enzyme-replacement therapy, Zettl says, and at the moment, most of the ADA used in the treatment is purified from cow spleens.

PPS’s ADA takes the animal out of the equation.

The cannabis side of the business, he adds, has helped PPS move forward with its therapeutic enzyme studies, with growing conditions, industry standards and pharmaceutical credibility supporting its scientific work.

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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.

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Children’s Hospital on cusp of gene therapy breakthrough

June 27, 2010

Children’s Hospital on cusp of gene therapy breakthrough

Local researchers are awaiting the green light to test a cutting-edge cure for a devastating disease that leaves babies unable to fight off the simplest infections.

Cincinnati Children’s Hospital Medical Center has gotten permission from the U.S. Food and Drug Administration to test a gene therapy treatment against X-linked severe combined immunodeficiency, or so-called “bubble-boy” disease. It’s the first federal approval the Corryville hospital has received for a gene therapy treatment conceived and manufactured in its own lab.

Now, Alexandra Filipovich and her colleagues are waiting for the hospital’s own institutional review board to sign off the trial.

“We’re ready to go,” said Filipovich, director of the hospital’s immunodeficiency and histiocytosis program and the primary investigator for the trial.

Maverick Steiner was only 4 months old when he was diagnosed with the disease after a long run of illnesses, including ear infections and diarrhea that wouldn’t go away. Doctors grew worried when he developed a form of pneumonia normally seen in AIDS patients – a sign his immune system was seriously compromised.

The immune disorder is caused by a defective gene that leaves babies unable to make two types of cells that attack bacteria, viruses and certain cancers.

For most babies, including Maverick, a bone marrow transplant cures the disease. But 20 to 30 percent of babies born with the disorder can’t get a transplant. Either they can’t find a donor match or they’re too sick to withstand the procedure.

For those babies, gene therapy could be the answer. It relies on technology that lets doctors custom-tailor viruses that, instead of causing sickness, cure it.

For Filipovich’s experiment, researchers will collect stem cells from babies with the immune disorder.

In the lab, those stem cells will be infected with specially designed viruses that carry a functioning copy of the defective gene that causes the immune disorder. The viruses have been engineered so that they can’t cause illness.

Doctors then will put the stem cells with the functioning gene back in the babies through an IV. If the experiment works, the new gene will let the babies’ immune systems function normally, and they’ll be able to fight off infections.

The viruses carrying the new gene were designed and built at Cincinnati Children’s.

The idea of using viruses to attack disease has great potential for treating cystic fibrosis, Huntington’s disease, sickle cell anemia and some forms of cancer, including brain tumors, said Han van der Loo, the lab’s director. It also has the potential to attract world-class researchers, coveted federal research dollars and private pharmaceutical contracts.

Dr. Punam Malik, a hematology-oncology expert and co-director of the lab, came to Cincinnati because of the viral vector lab.

Malik, now the lab’s co-director, is heading up a clinical trial testing gene therapy as a potential cure for sickle-cell anemia. The trial could start in the spring of 2011.

Malik is organizing a clinical trial to test gene therapy as a potential cure for sickle cell anemia. She’s still waiting for approval from federal regulators.

It’s taken Malik and her colleagues 10 years to get to this point – and the therapy hasn’t been injected into a human being yet. It has been tested in lab animals, but the altered viruses had to be designed and manufactured, and that process costs money.

Without the in-house lab, Malik said, she and her colleagues would have had to contract with another research-grade lab, which would have required them to put the science on hold while they found money. “We can’t afford to do that,” she said.

To produce the altered viruses in both the quantity and quality suitable for use in humans, Malik and other researchers without access to an in-house lab would likely need to turn to the pharmaceutical industry. But the industry isn’t likely to be interested in producing an extremely expensive drug that might not work.

“They don’t want to take a risk. They want a return on investment, and we have no idea if we will have a return on investment,” she said.

Because Cincinnati Children’s has its own viral vector lab and its own lab for processing pharmaceutical-quality stem cells, the pressure to make a profit is off. Researchers like Malik just have to find enough money to cover the cost of labor and materials.

The viral vector lab, a 10,000-square foot facility with nine “clean rooms” in which technologists make the altered viruses, has the capacity to make a gene therapy drug in sufficient quantities for small-scale human testing. Filipovich hopes to recruit three patients through the hospital for the first phase of her immune disorder experiment.

If a gene therapy drug were found to be safe and effective enough to go onto large-scale trials – meaning it was likely to win FDA approval and make it to the market – the hospital would likely license, or sell, the drug to a pharmaceutical company.

Such a sale, which could mean millions of dollars.

The hospital is already expecting other kinds.

Because of the XSCID trial, Filipovich and her colleagues are getting invitations from researchers in Europe to participate in a number of projects. There’s no way to put a price tag on that kind of opportunity, she said.

For parents, there’s no way to put a price tag on their children’s health.

Maverick, now 16 months old, is doing well since the bone marrow transplant, said his mother, Jessica Steiner. She and her husband, Ryan, live in St. Bernard.

But Maverick spent nearly four months in the hospital while he was waiting for the bone marrow transplant, which he underwent in October.

“He’s doing great now,” she said.

CORRECTION: An earlier version of this story incorrectly spelled the name of Dr. Punam Malik

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