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New Gene Therapy for "Bubble Boy" Disease Appears to be Safe, Effective

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PHILADELPHIA A new form ofgene therapyfor boys with X-linked severe combined immunodeficiency syndrome (SCID-X1), a life-threatening condition also known as bubble boy disease, appears to be both effective and safe, according to an international clinical trial with sites inBoston, Cincinnati, Los Angeles, London, and Paris.

Early data published in theNew England Journal of Medicinesuggests that the therapy may avoid the late-developing leukemiaseen in a quarter of SCID-X1 patients in previous gene-therapy trials in Europe that took place more than a decade ago. Left untreated, boys with SCID-X1 usually die of infection before their first birthday.

The lab of coauthorFrederic Bushman, PhD, professor of Microbiology, from thePerelman School of Medicine at the University of Pennsylvania, carried out the deep DNA sequencing on patient specimens to track and verify distributions of integration sites of the vector.The vector used in the new trial was engineered to remove molecular signals implicated in cancers in the first trial.

Eight of nine boys recruited to date to the present trial are alive between 12 and 38 months after treatment, with no SCID-X1-associated infections. The gene therapy alone generated functioning immune systems in seven of eight boys. Genetic studies showed that the new viral vector did not lead to vector insertions near known cancer-causing genes, raising cautious hopes about the vector's long-term safety.

We showed that fewer cells accumulated with integration sites near cancer genes in the second trial, suggesting that the adverse properties had indeed been engineered out, explains Bushman So far there are no clinical adverse events in the present trial -- the integration site data has suggested improved safety.

The modified vector created for the current trial is a self-inactivating gammaretrovirus, designed to deliver its payload effectively while minimizing the chance of inadvertently turning on oncogenes that could lead to leukemia.

The core question of the trial was whether the new self-inactivating viral vector could safely and successfully shuttle a gene called theIL-2 receptor gamma(IL2RG) subunit into the patients' hematopoietic stem cells. In boys born with SCID-X1, mutations render theIL2RGgene inactive, robbing the children of the ability to produce a functional immune system.

For more information, see theDana-Farber/Boston Children's Cancer and Blood Disorders Centersnews release.

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Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of theRaymond and Ruth Perelman School of Medicine at the University of Pennsylvania(founded in 1765 as the nation's first medical school) and theUniversity of Pennsylvania Health System, which together form a $4.3 billion enterprise.

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New Gene Therapy for "Bubble Boy" Disease Appears to be Safe, Effective

Gene therapy offers a safe and effective way to treat bubble boy disease Health Updates – Video

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Gene Therapy Shows Potential for 'Bubble Boy' Disease

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Amy Norton HealthDay Reporter Posted: Thursday, October 9, 2014, 5:00 AM

(HealthDay News) -- A new form of gene therapy may offer a safe and effective way to treat "bubble boy" disease -- a severe immune deficiency that is fatal unless treated in infancy.

Researchers have long known that gene therapy can cure the disease, known medically as severe combined immunodeficiency, or SCID. Over a decade ago, trials in Europe showed that gene therapy worked -- but five of the 20 children treated developed leukemia (a type of cancer) within two to five years, according to background information in the study.

In the new trial, reported in the Oct. 9 New England Journal of Medicine, researchers refined the gene therapy approach to hopefully negate the leukemia risk.

Eight of nine children who received the therapy are still alive one to three years later, the investigators report. And so far, none has developed leukemia.

It's too early to say the therapy carries no leukemia risk, cautioned researcher Dr. David Williams, a pediatric hematologist/oncologist at Dana-Farber Cancer Institute and Boston Children's Hospital.

"We'll continue to follow these children for 15 years," Williams said.

But based on the early results, he noted, the tweaked gene therapy appears as effective at generating a functional immune system as the earlier form of treatment.

SCID refers to a group of rare genetic disorders that all but eliminate the immune system, according to the Immune Deficiency Foundation (IDF). That leaves children at high risk of severe infections.

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Gene Therapy Shows Potential for 'Bubble Boy' Disease

Gene therapy shows promise for severe combined immunodeficiency

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PUBLIC RELEASE DATE:

8-Oct-2014

Contact: Hillary Hoffman hillary.hoffman@nih.gov 301-402-1663 NIH/National Institute of Allergy and Infectious Diseases @NIAIDNews

Researchers have found that gene therapy using a modified delivery system, or vector, can restore the immune systems of children with X-linked severe combined immunodeficiency (SCID-X1), a rare, life-threatening inherited condition that primarily affects boys. Previous efforts to treat SCID-X1 with gene therapy were initially successful, but approximately one-quarter of the children developed leukemia two to five years after treatment. Results from a study partially funded by the National Institute of Allergy and Infectious Diseases (NIAID), a component of the National Institutes of Health (NIH), suggest that the new vector is equally effective at restoring immunity and may be safer than previous approaches.

In SCID-X1, mutations in a specific gene prevent the development of infection-fighting T cells. The standard therapy for SCID is transplantation of blood-forming stem cells, but some patients lack a suitable donor. In gene therapy, doctors remove stem cells from the patient's bone marrow, use a vector to insert a corrected gene and then return the corrected cells to the patient. Scientists suspect that the vectors used in earlier studies may have activated genes that control cell growth, contributing to leukemia.

In the current study, nine boys with SCID-X1 underwent gene therapy using a vector engineered by the study researchers. Seven boys developed functional T cells at levels comparable to those seen in previous studies and have remained healthy for one to three years after treatment. Analyses of the children's T cells suggest that the new vector causes fewer genomic changes that could be linked to leukemia. Researchers will continue to monitor the boys for leukemia development. Of the two other boys, one died of a pre-existing viral infection shortly after receiving the therapy, and one failed to develop corrected T cells and was given a stem cell transplant from an unrelated donor.

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ARTICLE:

S Hacein-Bey-Abina, S-Y Pai et al. A modified y-retrovirus vector for X-linked severe combined immunodeficiency. New England Journal of Medicine DOI: 10.1056/NEJMoa1404588 (2014).

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Gene therapy shows promise for severe combined immunodeficiency

Scientists find possible new therapy for rare lung disease in children

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Researchers at Cincinnati Childrens Hospital Medical Center have discovered a new gene and cell therapy that could treat a rare lung disease in children.

In the study, published in the journal Nature, researchers found that transplanting pulmonary macrophages immune cells into the lungs of mice corrected hereditary pulmonary alveolar proteinosis (hPAP).

The lung disease is caused by a build-up of surfactant, an oily substance in the air sacs of the lungs, which results in reduced lung function and eventually failure. The condition is the opposite of a common condition in premature babies, whose lungs are at a higher risk of collapsing because their air sacs will not stay open. Children with hPAP, on the other hand, have such high levels of surfactants that the childrens air sacs overinflate, and they drown internally as a result.

Between 2,000 and 3,000 children in the U.S. have hPAP, senior study author Bruce Trapnell, a physician in the division of neonatology and pulmonary biology at Cincinnati Children's Hospital Medical Center, told FoxNews.com.

The only available therapy for the rare disease whole-lung lavage is a difficult procedure thats invasive, requires anesthesia and involves mechanical ventilation, Trapnell said. For the surgery, doctors must attach a breathing tube to one lung and fill the other with salt water. A few days later, the procedure is repeated on the opposite lung.

Its like trying to wash butter out of a sponge by squirting it with a garden hose, Trapnell said.

Searching for a different type of therapy, researchers studied transplantation of naturally healthy macrophages or gene-corrected macrophages into the lungs of mice with hPAP. The therapy corrected the disease in mice for at least one year and prevented disease-related death.

Researchers are planning clinical trials of macrophage transplantation, but they noted that questions remain. Previous research using bone marrow transplantation was successful in animal models, but failed in human trials.

We have to address how many cells to transfer, and how the human body processes these cells," study co-author Takuji Suzuki, a scientist in the division of neonatology and pulmonary biology at Cincinnati Childrens, told FoxNews.com.

Researchers hope to begin the clinical health study in two to three years.

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Scientists find possible new therapy for rare lung disease in children


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