News in Brief
Stopping Leukemia in its Tracks
Researchers have discovered a way to block the activity of the cancerous cell that generates some forms of acute myeloid leukemia.
“It seems we have found the Achilles’ heel of this form of cancer,” says H. Leighton Grimes, PhD, of the Division of Immunobiology at Cincinnati Children’s. And it appears to be tiny bits of genetic material.
The discovery began last year when Grimes developed the first mouse model for a disease called severe congenital neutropenia. Twenty percent of patients with this disease also develop acute myeloid leukemia. Although past attempts to reproduce congenital neutropenia in mice had failed, Grimes’ lab was successful when they mutated a gene called GFI1. “GFI1 is like a light switch that turns off the expression of other genes,” Grimes says.
With this new GFI1-deficient mouse model, a pathway to acute myeloid leukemia unfolded. Grimes found that GFI1 normally blocked the signals from other pieces of genetic material, called microRNAs. In certain types of acute myeloid leukemia, cancer formation seemed to hinge on the messages that two specific microRNAs were sending. “GFI1 is actively fighting to suppress these microRNAs,” says Grimes. “If we overexpress GFI1 in cancerous cells, it suppresses the microRNAs and the transformation [from regular cells to cancerous cells].”
Stopping the microRNAs stopped the cancer, says Grimes, even without forcing GFI1 expression. In mouse models of leukemia, in which each in vitro colony has the capacity to initiate leukemia in a recipient, the number of colonies is dramatically lower by getting rid of these microRNAs. The translation of that is, if you treat the kids with these small-molecule inhibitors, you could eradicate the disease.”
Unlike chemotherapy that targets both healthy and cancerous cells, causing a variety of side effects, the microRNA inhibitors have not caused problems in Grimes’ mice. Although he cautions that years of testing will be needed before the findings can be applied to clinical use, Grimes says the discovery could lead to better treatments with fewer side effects.
Cohen Takes On New Clinical Affairs Role
Mitchell B. Cohen, MD, has been appointed vice chair for clinical affairs at Cincinnati Children’s. This new position is designed to improve models of care, integrate clinical and research priorities, help grow clinical services, recruit and retain faculty, and measure and evaluate outcomes.
After completing a fellowship and research scholarship at Cincinnati Children’s, Cohen joined the faculty in 1987. He has led an NIH-funded research program, the Digestive Health Center and Fellowship Training Grants, and served in national leadership and policy roles relating to both clinical and research planning.
He was appointed director of Gastroenterology, Hepatology and Nutrition in 2005, a role he will maintain in addition to his new duties. As director, Cohen has led his division in developing a strategic plan to improve access to care, optimize care delivery and outcomes, support effective collaboration with other divisions, and link clinical care and research.
“Mitch will bring his knowledge of the institution, as well as his strengths as a clinician, educator, researcher, leader and strategic thinker to this role,” says Arnold Strauss, MD, director of the Cincinnati Children’s Research Foundation and chair of pediatrics.
“This is an exciting opportunity to make Cincinnati Children’s an even greater center for outstanding patient care, faculty success and satisfaction and innovation,” says Cohen.
Reducing the Toxic Effects of Anti-Rejection Drugs
Pediatric and adult organ transplant recipients need medications to prevent rejection, but these drugs may also cause adverse effects such as cardiovascular disease or kidney damage. Mycophenolate mofetil (MMF), a commonly used anti-rejection medication, is associated with gastrointestinal and hematological toxicity. Physicians may reduce the dosage to minimize toxicity, but that can increase the risk of rejection.
To understand how to use MMF more effectively, Jens Goebel, MD, medical director of kidney transplantation, and David Hooper, MD, fellow in the Division of Nephrology and Hypertension at Cincinnati Children’s, are leading a multicenter collaborative project through the Midwest Pediatric Nephrology Consortium.
Designed to better understand the pharmacogenetic aspects of MMF toxicity in children with kidney transplants, the study builds on pilot work by researchers in the Cincinnati Children’s Division of Clinical Pharmacology under the direction of Alexander Vinks, PharmD, PhD. The pilot work demonstrates an association between genetic variants in the main MMF-metabolizing enzyme uridine glucuronyl transferase and the risk of MMF-associated leukopenia.
Their work, recently published online in Clinical Pharmacology and Therapeutics, and Hooper’s ongoing project, are cornerstones of efforts led by Vinks and Goebel to better understand the pharmacogenetics of MMF. Ultimately, the researchers expect these efforts to allow prediction of individual patients’ responses to MMF and possibly personalized dosing to avoid toxicity. “One size, even when adjusted for body surface area, clearly doesn’t fit all when it comes to MMF dosing,” says Goebel.
Support for the study comes from grants from the Kidney Foundation of Greater Cincinnati, the Center for Research and Education in Therapeutics at Cincinnati Children’s and the University of Cincinnati Center for Environmental Genetics.
Balistreri Receives AGA Distinguished Educator Award
William Balistreri, MD, medical director of the Pediatric Liver Care Center, is the recipient of the 2009 American Gastroenterological Association (AGA) Distinguished Educator Award. The award honors his outstanding contributions and achievements as an educator over a lifelong career. He is the first pediatrician in the long history of the organization to receive this award. The AGA, founded in 1897, is the oldest medicalspecialty society in the United States.
“Dr. Balistreri has helped shaped the field of digestive diseases in general, and hepatology in particular, through an unwavering commitment to specialty training and remarkable service to national societies,” says Mitchell Cohen, MD, director of the Division of Gastroenterology, Hepatology and Nutrition at Cincinnati Children’s.
New Director of Liver Transplant Program
Kathleen Campbell, MD, has accepted the position of medical director of the Pediatric Liver Transplant Program. Campbell assumes the role July 1, 2009 from William Balistreri, MD, who will remain active in the program.
Campbell is board certified in pediatric gastroenterology, with a certificate of added qualification in pediatric transplant hepatology. She will be charged with meeting the program’s evolving needs and building on the exceptional research and clinical reputation created by Balistreri along with colleagues Fred Ryckman, MD, John Bucuvalas, MD and Maria Alonso, MD.
“I am honored and excited to take on this role,” says Campbell. “I look forward to following in their footsteps and ensuring that our program is the best pediatric transplant program in the country.”
Scientists Link Gene to Severity of Cystic Fibrosis
A research team has found a gene that modifies the severity of cystic fibrosis, pointing to possible new targets for treatment.
Deleting the gene in mice confirmed its role in regulating inflammation and disease. After the animals’ airways were infected with the bacterium that is a major cause of lung infection in cystic fibrosis, the mice experienced less inflammation and disease, says senior investigator Christopher Karp, MD, director of Molecular Immunology at Cincinnati Children’s.
Appearing in Nature in February, this is the first published study to use a genome-wide approach to look for genes that modify the severity of cystic fibrosis lung disease.
After analyzing the genetic makeup of nearly 3,000 cystic fibrosis patients, the researchers found that small genetic differences in a gene called IFRD1 correlate with lung disease severity. While probing how the gene might alter the disease’s course, researchers discovered the protein encoded by IFRD1 is particularly abundant in a type of white blood cell called neutrophils, and that it regulates their function.
“Neutrophils are important to the immune system’s response to bacterial infection,” says Karp. “In cystic fibrosis, however, neutrophilic airway inflammation is dysregulated, eventually destroying the lung.”
To further explore IFRD1’s role in the disease process, the researchers studied mice in which the IFRD1 gene was knocked out. “It’s possible that IFRD1 itself could become a target for treatment, but right now it’s a signpost to pathways for further study,” Karp says. “We want to find out what other genes and proteins IFRD1 interacts with, and how this is connected to inflammation in cystic fibrosis lung disease.”
Funding support for the study came from the National Cystic Fibrosis Foundation, the National Heart Lung and Blood Institute, the Wake Forest University Health Sciences Center for Health Genomics and the Austrian Science Fund.
Alternate Path Discovered for T Cell Development
Researchers at Cincinnati Children’s have discovered a way to bypass the autoimmune process. The treatment resulting from this new finding could benefit thousands of children who become sick or die from autoimmune disorders and chronic infections.
A study published in PLoS (Public Library of Science) Biology in March reported genetic evidence that two distinct molecular pathways control the formation of regulatory T cells Treg), a vitally important cell type in limiting undesirable immune responses.
Under normal healthy conditions, most Treg cells are derived from the thymus. However, the study shows that in the absence of a gene called Carma1, Treg development in the thymus is impaired, says senior investigator Kasper Hoebe, PhD, a researcher in the Division of Molecular Immunology at Cincinnati Children’s.
But the study also points to a second molecular pathway – occurring in the peripheral lymphoid system – that can result in development of Treg cells. This means if the process in the thymus breaks down, as it does with Carma1 mutations, inducing Treg cells through the peripheral lymphoid system may fill the void.
“This is important because it shows the flexibility of the immune system to regulate T cell responses,” Hoebe says. “If we understand the molecular requirements of these pathways, we can potentially use them as targets for therapeutic intervention – which is the eventual goal.”
Support for the study came fromthe National Institutes of Health.
New Director Named for Center for Technology Commercialization
When a breakthrough scientific finding happens at Cincinnati Children’s, how does it go from the lab to the marketplace?
That’s the job of Niki Robinson, PhD, newly appointed executive director of the Center for Technology Commercialization (CTC) at Cincinnati Children’s. The CTC identifies, assesses, protects and commercializes discoveries and innovations and, with commercial partners, focuses on bringing new discoveries for improved health to pediatric patients.
Robinson earned her PhD in the Department of Neurobiology, Pharmacology and Physiology at the University of Chicago. She joined the CTC as licensing manager in 2006 and has served as interim director since 2007. In that role, she implemented an office-wide data and process improvement project that increased efficiencies and recovered more than $1 million in revenue. She is eager to build on this solid foundation.
“We look forward to continued partnerships with our investigators, renewed partnerships with the region’s entrepreneurial companies, and new partnerships with the venture community, companies and collaborators to expand our commercial opportunities. This work aligns with the mission of Cincinnati Children’s,” Robinson says.
Researchers Discover Cause of HSV Recurrence
Researchers from Cincinnati Children’s and the University of Cincinnati College of Medicine have identified a viral protein, VP16, as the molecular key that prompts latent herpes simplex virus (HSV) to reactivate and cause recurrent disease.
In a study published in Public Library of Science (PLoS) Pathogens, the researchers solve the long standing medical mystery of what causes HSV to periodically reactivate in latently infected neurons, prompting new rounds of virus replication at the body surface.
“Our current findings show that, in elegant simplicity, the herpes simplex virus regulates this complex lifecycle through the expression of VP16,” said Nancy Sawtell, PhD, study author and researcher in the Division of Infectious Diseases at Cincinnati Children’s.
By understanding how HSV achieves this interaction inside the human nervous system, researchers can gain crucial insight into controlling the spread of the virus. At present, there is no way to eliminate latent virus or to prevent the virus from reactivating.
The new finding provides scientists with a molecular target for designing improved HSV vaccines and treatments. It also could direct refined engineering of HSV viruses used in cancer therapy, the investigators said.
The study was conducted in collaborationwith the Medical Research Council Virology Unit of Glasgow, Scotland.
A Cellular Kick in the Pants
To wake up the stem cells in the brain so they will regenerate as nerve cells, Masato Nakafuku, MD, PhD, and his team injected a growth factor cocktail into the brain’s ventricular opening, a fluid-filled space where a large number of stem cells reside.
The cocktail combined fibroblast growth factor, important in embryonic development and the growth of new blood vessels and wound healing, and epidermal growth factor, which is crucial for cell division and differentiation.
The mixture is designed to help the otherwise dormant stem cells overcome whatever prevented them from responding to the injury in the first place.
“They have barriers,” he says. “Although it’s not clear what those barriers are, they see them. And we help them overcome the barriers in this situation.”
Success in activating the stem cells requires getting the balance just right. “If you don’t use the right dose, or choose the right place, or the right timing, you don’t get this,” Nakafuku says. “Using more, or dosing longer, actually has a negative impact, even suppressing the recovery.”
He adds that the cocktail boost doesn’t force the cells to regenerate; it just helps the growth process.
“We just push them a bit,” Nakafuku says. “The rest is up to them.”
