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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

Researchers develop novel gene/cell therapy approach for lung disease

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PUBLIC RELEASE DATE:

1-Oct-2014

Contact: Nick Miller nicholas.miller@cchmc.org 513-803-6035 Cincinnati Children's Hospital Medical Center @CincyChildrens

CINCINNATI Researchers developed a new type of cell transplantation to treat mice mimicking a rare lung disease that one day could be used to treat this and other human lung diseases caused by dysfunctional immune cells.

Scientists at Cincinnati Children's Hospital Medical Center report their findings in a study posted online Oct. 1 by Nature. In the study, the authors used macrophages, a type of immune cell that helps collect and remove used molecules and cell debris from the body.

They transplanted either normal or gene-corrected macrophages into the respiratory tracts of mice, which were bred to mimic the hereditary form of a human disease called hereditary pulmonary alveolar proteinosis (hPAP). Treatment with both normal and gene-corrected macrophages corrected the disease in the mice.

"These are significant findings with potential implications beyond the treatment of a rare lung disease," said Bruce Trapnell, MD, senior author and a physician in the Division of Neonatology and Pulmonary Biology at Cincinnati Children's. "Our findings support the concept of pulmonary macrophage transplantation (PMT) as the first specific therapy for children with hPAP"

"Results also identified mechanisms regulating the numbers and phenotype of macrophages in the tiny air sacs of the lungs (called alveoli) in health and disease," said Takuji Suzuki, MD, PhD, the study's first author and a scientist in the Division of Neonatology and Pulmonary Biology at Cincinnati Children's.

Suzuki and Trapnell discovered hPAP at Cincinnati Children's and first reported it in 2008. In hPAP, the air sacs become filled with surfactant, a substance the lungs produce to reduce surface tension and keep the air sacs open. Children with hPAP have mutations in the genes of GM-CSF receptor alpha or beta (CSFR2RA or CSFR2RB). These mutations reduce the ability of alveolar macrophages to remove used surfactant from the lungs of these children.

The used surfactant builds up in the lungs, filling the alveoli and causing difficult breathing or respiratory failure. The only current treatment for these children is whole-lung lavage, an invasive lung-washing procedure performed under general anesthesia. Although the procedure works, it is temporary, must be repeated frequently, and creates quality of life issues for affected children.

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Researchers develop novel gene/cell therapy approach for lung disease

Liver gene therapy corrects heart symptoms in model of rare enzyme disorder

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PUBLIC RELEASE DATE:

29-Sep-2014

Contact: Karen Kreeger karen.kreeger@uphs.upenn.edu 215-349-5658 University of Pennsylvania School of Medicine @PennMedNews

PHILADELPHIA In the second of two papers outlining new gene-therapy approaches to treat a rare disease called MPS I, researchers from Perelman School of Medicine at the University of Pennsylvania examined systemic delivery of a vector to replace the enzyme IDUA, which is deficient in patients with this disorder. The second paper, which is published online in the Proceedings of the National Academy of Sciences this week, describes how an injection of a vector expressing the IDUA enzyme to the liver can prevent most of the systemic manifestations of the disease, including those found in the heart.

The first paper, published in Molecular Therapy, describes the use of an adeno-associated viral (AAV) vector to introduce normal IDUA to glial and neuronal cells in the brain and spinal cord in a feline model. The aim of that study was to directly treat the central nervous system manifestations of MPS while the more recent study aims to treat all other manifestations of the disease outside of the nervous system.

This family of diseases comprises about 50 rare inherited disorders marked by defects in the lysosomes, compartments within cells filled with enzymes to digest large molecules. If one of these enzymes is mutated, molecules that would normally be degraded by the lysosome accumulate within the cell and their fragments are not recycled. Many of the MPS disorders can share symptoms, such as speech and hearing problems, hernias, and heart problems. Patient groups estimate that in the United States 1 in 25,000 births will result in some form of MPS. Life expectancy varies significantly for people with MPS I.

The two main treatments for MPS I are bone marrow transplantation and intravenous enzyme replacement therapy (ERT), but these are only marginally effective or clinically impractical, and have significant drawbacks for patient safety and quality of life and do not effectively address some of the most critical clinical symptoms, such as life-threatening cardiac valve impairments.

"Both of these papers are the first proof-of-principle demonstrations for the efficacy and practicality for gene therapies to be translated into the clinic for lysosomal storage diseases," says lead author James M. Wilson, MD, PhD, professor of Pathology and Laboratory Medicine and director of the Penn Gene Therapy Program. "This approach may likely turn out to be better than ERT and compete with or replace ERT. We are especially excited about the use of this approach in treating the many MPS I patients who do not have access to ERT due to cost or inadequate health delivery systems to support repeated protein infusions, such as in China, Eastern Europe, India, and parts of South America."

Patients with mucopolysaccharidosis type I (MPS I), accumulate compounds called glycosaminoglycans in tissues, with resulting diverse clinical symptoms, including neurological, eye, skeletal, and cardiac disease.

Using a naturally occurring feline model of MPS I, the team tested liver-directed gene therapy via a single intravenous infusion as a means of establishing long-term systemic IDUA presence throughout the body.

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Liver gene therapy corrects heart symptoms in model of rare enzyme disorder

Gene Therapy Targeting Liver Corrects Cardiovascular Symptoms in Animal Model of Rare Enzyme Deficiency Disease

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PHILADELPHIA In the second of two papers outlining new gene-therapy approaches to treat a rare disease called MPS I, researchers from Perelman School of Medicine at the University of Pennsylvania examined systemic delivery of a vector to replace the enzyme IDUA, which is deficient in patients with this disorder. The second paper, which is published online in the Proceedings of the National Academy of Sciences this week, describes how an injection of a vector expressing the IDUA enzyme to the liver can prevent most of the systemic manifestations of the disease, including those found in the heart.

The first paper, published in Molecular Therapy, describes the use of an adeno-associated viral (AAV) vector to introduce normal IDUA to glial and neuronal cells in the brain and spinal cord in a feline model. The aim of that study was to directly treat the central nervous system manifestations of MPS while the more recent study aims to treat all other manifestations of the disease outside of the nervous system.

This family of diseases comprises about 50 rare inherited disorders marked by defects in the lysosomes, compartments within cells filled with enzymes to digest large molecules. If one of these enzymes is mutated, molecules that would normally be degraded by the lysosome accumulate within the cell and their fragments are not recycled. Many of the MPS disorders can share symptoms, such as speech and hearing problems, hernias, and heart problems. Patient groups estimate that in the United States 1 in 25,000 births will result in some form of MPS. Life expectancy varies significantly for people with MPS I.

The two main treatments for MPS I are bone marrow transplantation and intravenous enzyme replacement therapy (ERT), but these are only marginally effective or clinically impractical, and have significant drawbacks for patient safety and quality of life and do not effectively address some of the most critical clinical symptoms, such as life-threatening cardiac valve impairments.

Both of these papers are the first proof-of-principle demonstrations for the efficacy and practicality for gene therapies to be translated into the clinic for lysosomal storage diseases, says lead author James M. Wilson, MD, PhD, professor of Pathology and Laboratory Medicine and director of the Penn Gene Therapy Program. This approach may likely turn out to be better than ERT and compete with or replace ERT. We are especially excited about the use of this approach in treating the many MPS I patients who do not have access to ERT due to cost or inadequate health delivery systems to support repeated protein infusions, such as in China, Eastern Europe, India, and parts of South America.

Patients with mucopolysaccharidosis type I (MPS I), accumulate compounds called glycosaminoglycans in tissues, with resulting diverse clinical symptoms, including neurological, eye, skeletal, and cardiac disease.

Using a naturally occurring feline model of MPS I, the team tested liver-directed gene therapy via a single intravenous infusion as a means of establishing long-term systemic IDUA presence throughout the body.

The team treated four MPS I cats at three to five months of age with an AAV serotype 8 vector expressing feline IDUA. We observed sustained serum enzyme activity for six months at approximately 30 percent of normal levels in one animal and in excess of normal levels in the other three animals, says Wilson.

Remarkably, treated animals not only demonstrated reductions in glycosaminoglycans storage in most tissues, but most also exhibited complete resolution of aortic valve lesions, an effect which has not been previously observed in this animal model or in MPS I patients treated with current therapies.

Critical to the evaluation of these novel therapies is the feline model of MPS I, which was provided through coauthor Mark E. Haskins, School of Veterinary Medicine at Penn. Haskins and his colleagues maintain a variety of canine and feline models of human genetic diseases that have been instrumental in establishing proof of concept for a number of novel therapeutics, including the current enzyme replacement therapy.

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Gene Therapy Targeting Liver Corrects Cardiovascular Symptoms in Animal Model of Rare Enzyme Deficiency Disease

EmTech: Risks of Gene-Editing Drugs Need Study, Pioneer Says

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One of the inventors of gene editing says scientists should proceed cautiously before testing it in people.

Feng Zhang

Citing the risk of deadly mistakes, a leading researcher speaking at MIT Technology ReviewsEmTech conferenceon Tuesday said the risks of gene editing need to be better understood before the technology can be used in medical studies.

Feng Zhang, a researcher at MIT, helped invent a powerful new way to alter DNA that he compared in his talk to a search-and-replace function for the genome.

Several startups have already sprung up to turn the technology into new kinds of gene-therapy drugs, including CRISPR Therapeutics and Editas Medicine, a biotechnology company that Zhang cofounded last year with venture capitalists who invested $43 million.

These companies hope to correct diseases, like cystic fibrosis, caused by faulty DNA. In other cases, Zhang said, changing a persons DNA could provide a protective effectfor instance, conferring immunity to HIV.

The concept is very powerful, but to make any correction in the body is very challenging, he said.

Looming over researchers is the 1999 death of Jesse Gelsinger, a volunteer in an early gene therapy study in Pennsylvania. That failure dealt a huge setback to genetic drugs. Later it was shown that such treatments, even when they work, could sometimes cause cancer by making unwanted changes to a persons genome.

One of the early lessons from gene therapy is to go slowly, said Zhang. The lesson is that we need to understand a system carefully before putting it into a person.

Gradually, however, gene therapy has staged a comeback. In 2012, a treatment called Glybera was the first to be approved in Europe. Its not yet for sale in the U.S., but numerous gene treatments are being tested in patients.

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EmTech: Risks of Gene-Editing Drugs Need Study, Pioneer Says

Mayo Clinic Center for Regenerative Medicine Collaboration with National University Ireland Galway – Video

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Mayo Clinic Center for Regenerative Medicine Collaboration with National University Ireland Galway
Mayo Clinic Center for Regenerative Medicine and National University Ireland Galway have signed a formal MOU to pave the way for joint clinical trials in regenerative medicine. They will focus...

By: Mayo Clinic

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Mayo Clinic Center for Regenerative Medicine Collaboration with National University Ireland Galway - Video


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