News in Brief

Funding to expand insights into childhood diabetes 

Cincinnati Children’s was awarded more than $3.2 million for the next five years to continue as one of six medical centers nationwide participating in the federal SEARCH for Diabetes in Youth study.

The project, launched a decade ago and entering its third round of funding, is considered the nation’s premier source of data about how children are affected by type 1 and type 2 diabetes, says Lawrence Dolan, MD, director of the Division of Endocrinology at Cincinnati Children’s and principal investigator for the study here.

The study tracks people under age 20 who have diabetes and how the disease varies by age, race and ethnicity. It gathers data from more than 3,000 children who continue in the study as they grow into adulthood, focusing on complications, transition to adult care, quality of life and quality of care.

The efforts are helping define more than 50 subtypes of diabetes and how they respond to treatments, Dolan says. They also help scientists understand why the disease is increasing and how obesity and other factors contribute.

“We’ve already found greater ethnic diversity in type 1 diabetes than was previously appreciated,” Dolan says. “Investigators in Europe found an increase in type 1 diabetes, and no one knows why. SEARCH is tracking the frequency of type 1 and other types of diabetes to see if a similar pattern is present
in the US.”

Meanwhile, some cases of diabetes result from gene mutations that cause the body’s insulin-producing cells to malfunction. As those genetic pathways are pinned down, it may become possible to use pluripotent stem cells to effectively cure these forms of diabetes without needing anti-rejection medications, Dolan says.

More than 38 scientific papers already have been published using information from the SEARCH study, and Dolan believes many more will come.

The SEARCH study is funded by the Centers for Disease Control and Prevention and the National Institute of Diabetes and Digestive and Kidney Diseases. The other medical centers involved are: University of North Carolina, University of Colorado Denver, Kaiser Permanente Southern California, Seattle Children’s Hospital and Wake Forest University Health Sciences.

Study to expand on ways to reduce injuries in home

Scientists at Cincinnati Children’s are finding that many childhood injuries can be prevented through a structured effort to make homes safer.

Researchers with the James M. Anderson Center for Health Systems Excellence have received a five-year, $3 million federal grant to expand upon a pilot study that reported an impressive reduction in home injuries. An initial two-year study involving more than 350 families found that installing stair gates, window guards, cabinet locks and other safety devices reduced hospital and medical visits for preventable injuries by 68 percent.

Now, the National Institutes of Health (NIH) is funding the Cincinnati Home Injury Prevention (CHIP) and Literacy Promotion Trial, which will expand the study to 1,000 first-time, low-income mothers in Greater Cincinnati. The mothers are participants in the Every Child Succeeds home visitation program.

“Our pilot study found that interventions can result in fewer falls, burns and accidental poisonings. Now we seek to replicate those results,” says Kieran Phelan, MD, MSc, principal investigator for the CHIP study.

The stakes are high. Injuries remain the nation’s leading cause of childhood morbidity and mortality, Phelan says, and home is where most injuries in young children occur. Childhood injuries account for more than 13 million clinic visits, 4 million emergency department visits, 74,000 hospital admissions and 2,800 deaths each year in the United States. The medical costs exceed $3 billion a year, and average about $800 per emergency visit.

Previous studies have shown that education alone has little impact on childhood injury rates. This program is different because, with participants’ permission, people go into their homes to inspect conditions and install safety devices, Phelan says. Labor and materials for the pilot study averaged about $600 per home.

Should this larger-scale study also show injury reductions, the findings could be used to revise housing codes or home safety policies at the national, state or local level and potentially build a market for home safety services.

Lab grows intestinal tissue from stem cells

For the first time, scientists have created functioning human intestinal tissue in the laboratory from pluripotent stem cells.

A team of Cincinnati Children’s scientists published their findings Dec. 12, 2010, in the online edition of the journal Nature. These findings represent a significant step toward generating intestinal tissue for transplantation, researchers say.

“This is the first study to demonstrate that human pluripotent stem cells in a petri dish can be instructed to efficiently form human tissue with three-dimensional architecture and cellular composition remarkably similar to intestinal tissue,” says James Wells, PhD, senior investigator on the study and a researcher in the Division of Developmental Biology at Cincinnati Children’s. Jason Spence, PhD, a member of Wells’ laboratory, was first author of the study.

“The hope is that our ability to turn stem cells into intestinal tissue will eventually be therapeutically beneficial for people with diseases such as necrotizing enterocolitis, inflammatory bowel disease and short bowel syndromes,” Wells says.

Cells used in the study were generated at the new Pluripotent Stem Cell Facility at Cincinnati Children’s by reprogramming biopsied human skin cells. Turning the stem cells into intestinal tissue required a timed series of cell manipulations using growth factors to mimic stages of embryonic intestinal development.

The first step generated an embryonic cell type called definitive endoderm, which gives rise to the lining of the esophagus, stomach and intestines as well as the lungs, pancreas and liver. Next, endoderm cells were instructed to become “hindgut progenitors,” and encouraged to multiply.

Within 28 days, these steps formed three-dimensional tissue resembling fetal intestine that contained all major cell types – including enterocytes, goblet, Paneth and enteroendocrine cells.

Next steps for this breakthrough research include using these cells as tools to study normal and abnormal intestinal development. Eventually, such cells also might prove useful in drug development as a new way to test how the body would absorb oral medications.

Cincinnati Children’s researchers Noah Shroyer, PhD, and Michael Helmrath, MS, MD, have already begun animal studies to evaluate the new cells as a treatment for short bowel syndrome.

Grant to fund new molecular hematology therapies 

The National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) approved a five-year, $3.4 million grant naming Cincinnati Children’s as one of five national Centers of Excellence for Molecular Hematology.

The center will be overseen by Yi Zheng, PhD, director of Experimental Hematology and Cancer Biology. It will focus on finding new gene and cell therapies for diseases such as sickle cell anemia, thalassemia, leukemia and immunological disorders. The goal is to move therapies more quickly 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,” says Zheng. “The medical center is one of the few institutions in the country that has excellence in basic science, expertise in genetic manipulation, outstanding cell and gene therapies and exceptional patient care in 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, Zheng says.

'Next generation' genetic research is here

Cincinnati Children’s significantly expanded its genetic research capabilities with the installation of an Illumina HiSeq 2000 and HiScan system for its Division of Human Genetics.

These DNA analysis systems have the highest output and fastest data generation in the field. The HiSeq 2000 can process one entire human genome in eight days. The HiScan can genotype 1 million single nucleotide polymorphisms (SNPs) – DNA pieces – for one patient in nine minutes.

That is five times faster than the medical center’s previous system, says Mehdi Keddache, MS, sequencing and genotyping core coordinator at Cincinnati Children’s.

The new system will mean faster results for genome-wide association studies that map gene variations associated with human disease. The system will also get fast results for RNA sequencing by generating detailed transcript profiles, including alternative splicing and RNA variants.

The technical ability to conduct large-scale gene research is exploding. In the 1990s, researchers could scan 293 genotypes a day. In 2009, top systems were identifying 1 million genotypes a day. The newest microarray scanners process 100 million per day.

“The technology is advancing so rapidly that the lifespan of these machines in terms of functionality is probably three years,” says Greg Grabowski, MD, director of the Division of Human Genetics.

The ultra precise robots and massively powerful computers that comprise the new HiSeq 2000 system cost more than $800,000, yet are small enough to sit on standard lab benches.

The robots process human DNA samples onto slides containing as many as a dozen tiny squares – or microarrays – each with hundreds of thousands of gene markers. When exposed to microscopic laser beams, these markers produce matrices of green and red fluorescent dots so dense they look like static on a computer screen. It requires powerful computers to “read” the static and report which genes are active and which are not.

This capacity allows SNPs collected from hundreds of people to be analyzed at once to spot gene regions that may be associated with disease. Deeper analysis of those regions can determine which specific gene mutations actually cause the disease.

“A few years ago, we could do only a few thousand SNPs in a day. By year’s end, this machine will have the capacity to do 5 million SNPs in a few minutes,” Keddache says.

Child-sizing radiation doses

A question from a parent about the safety of his child’s CT scan compelled radiologist Marilyn Goske, MD, to start an education and awareness campaign called “Image Gently.”

Sponsored by the Alliance for Radiation Safety in Pediatric Imaging, the campaign promotes radiation protection for children worldwide. In three years, it has grown to 60 medical professional societies and agencies. In addition, the alliance works with the makers of imaging equipment and regulatory agencies.

Goske, the Corning Benton Chair for Radiology Education at Cincinnati Children’s, says there is no doubt that CT scans save lives. They are often the best – and only – way to help diagnose trauma,
cancer or other life-threatening illnesses.

What she cannot say is whether radiation from computed tomography puts a child at greater risk for cancer. So she and her radiology colleagues at Cincinnati Children’s have taken a “better safe than sorry” approach. They have been at the forefront of lowering radiation doses when imaging children.

“When you talk about radiation risk in medical imaging, much of it is based on theory. We don’t have any hard data to link whether medical radiation causes cancer,” she says. “You can debate this for
another 20 years, and that paralyzes you. Our tack has been to say we’re not sure. We don’t know. Let’s act as if it might and do what we can for radiation protection. We can look for alternate imaging that does not use CT, and we can ensure that when imaging is performed that it is for a clear reason to benefit the child. If the scan is medically needed, we work to get a high-quality CT at a child-size dose.”

Goske’s work may lead to changing practice. She is principal investigator in a $150,000 grant from the Radiological Society of North America, funded through this year. She and her co-investigators have developed a “best practice” national registry for CT scans in children. Cincinnati Children’s is part of a consortium of six children’s hospitals in the first children’s registry in pediatric radiology in CT scanning. They plan to turn best practices into universal protocols.

Cancer-targeting compound wins more funding

A small company formed to further develop a novel, experimental cancer therapy discovered at Cincinnati Children’s has received federal and state funding to prepare the product for initial clinical trials.

Bexion Pharmaceuticals LLC, based in Covington, KY, has been selected for a research collaboration with the National Cancer Institute’s Nanotechnology Characterization Laboratory (NCL). The project will generate vital data for Bexion’s Investigational New Drug application with the US Food and Drug Administration (FDA).

The compound, Saposin C-dioleoylphosphatidylserine (also known as SapC-DOPS), was discovered in 2002 by Xiaoyang Qi, PhD, a human geneticist at Cincinnati Children’s. The medical center obtained a patent for the compound in 2005. Bexion then licensed the technology from Cincinnati Children’s in 2006.

This nanovesicle compound homes in on the acidic nature of cancer cells, then induces apoptosis, essentially tricking the cells into killing themselves. In tests involving animals and cultured human cells, the compound has destroyed cancer cells – including glioblastoma and pancreatic cancer cells – without harming healthy tissue. A study describing the cancer-targeting ability of SapC-DOPS was published in September 2009 in the journal Clinical Cancer Research. In December, the Kentucky Economic Development Finance Authority awarded Bexion up to $155,000 to assist in purchasing lab equipment.

The NCL study will focus on the absorption, distribution and toxicity properties of SapC-DOPS. If the FDA
approves, Bexion plans to begin Phase I clinical trials by mid-2011.