In the McDonnell Pediatric Cancer Center
Washington University School of Medicine bioengineers Yongjian Liu, PhD and Hong Chen, PhD, will use their CDI funding to develop an innovative strategy for the single greatest cause of brain tumor-related deaths in children, diffuse intrinsic pontine glioma (DIPG). Traditionally, the location and diffuse nature of DIPG prohibit surgery. Moreover, the disease does not respond to radiation and chemotherapy. This research team will test the effectiveness and safety of using focused ultrasound to noninvasively, locally, and temporally open the blood-brain barrier — a barrier that prevent most drugs from reaching the brain tissue — enough for ultra-small nano-clusters loaded with an imaging agent and chemotherapy drugs to infiltrate the tumor, allowing for imaging-guided therapy.
A second newly funded pediatric cancer study has the potential to cure pediatric and young adult acute myeloid leukemia (AML) in patients who relapse after a bone marrow transplant. Despite all the gains made in pediatric cancer research, AML continues to present difficult challenges. Most children and young adults diagnosed with AML must undergo a bone marrow transplant. Survival for patients who relapse after bone marrow transplant too-often is poor. Researchers Todd Fehniger, MD, PhD, medicine; and co-investigators Jeffrey Bednarski, MD, PhD, pediatrics; and Rizwan Romee, MD, medicine, will conduct a personalized clinical trial to determine whether a cellular immunotherapy strategy shown to be promising in adults will be effective in children. This treatment uses a type of white blood cell called “natural killer” cells, which can be trained and activated in the lab and then essentially unleashed to destroy leukemia cells in the patient.
In another newly funded clinical trial in pediatric cancer research, Karen Gauvain, MD, PhD, pediatrics; and Gavin Dunn, MD, PhD, neurosurgery, hope their study will lead to more effective treatments for children with recurrent brain tumors. Currently, very few options are available. This project is the first-ever clinical trial to treat pediatric patients experiencing relapsed or recurrent brain tumors with a personalized vaccine — referred to as a peptide vaccine — developed by targeting genetic abnormalities in each individual tumor. The researchers will benefit from the School of Medicine’s emergence as a world leader in developing personalized vaccines to fight cancer.
In the Congenital Heart Disease Center
Pediatric cardiologist Jennifer Silva, MD, pediatrics; has teamed up with co-investigator (and husband) Jonathan Silva, PhD, biomedical engineering, in the hopes of applying recent advances in augmented reality to improve the outcome of minimally-invasive trans-catheter ablations to treat chronic arrhythmias in children. CDI funding will enable the testing of specially designed goggles that project three-dimensional holograms of the patient’s heart, enhancing pediatric cardiologists’ line of sight into the heart. The technology will be used in the St. Louis Children’s Hospital Heart Center cardiac electrophysiology and catheterization laboratory, where patients routinely undergo procedures for heart rhythm abnormalities and congenital heart defects.
A second congenital heart disease study takes aim at pediatric dilated cardiomyopathy (DCM), a life-threatening condition that puts children on the path to heart transplant. Responding to the need to identify therapies for childhood heart failure, Kory Lavine, MD, PhD, medicine, has been studying macrophages. These are important cells of the immune system because they recognize and respond to infection by engulfing and destroying accumulating harmful or dead cells. In previous studies, Dr. Lavine showed that some macrophages can be put to work to repair cardiac tissue. Others are detrimental. Through new CDI funding and using mouse models, he teams up with Christopher Sturgeon, PhD, medicine, to determine whether macrophages associated with cardiac repair can be derived from one’s own stem cells.
In the Center for Metabolism and Immunity and Center for Pediatric Pulmonary Disease
Neutrophils are an important type of white blood cells that respond to both infection and inflammation, and can contribute inflammatory tissue injury. Addressing the fact that 30 percent of all pediatric intensive care unit deaths are the result of acute lung injury, Regina Clemens, MD, PhD, pediatrics, will use her CDI faculty scholar award to learn more about how neutrophils are activated during inflammation and how this can be regulated to prevent tissue-damaging side effects.
Continuing his CDI-supported work treat non-alcoholic fatty liver disease (NAFLD), Brian DeBosch, MD, PhD, pediatrics, will team up with Paul Hruz, MD, PhD, pediatrics, to study the sugar transporting protein, GLUT8. The research team will test the hypothesis that selective GLUT8 inhibition reverses fat accumulation in the liver. If they can identify selective, high-potency small-molecule GLUT8 inhibitors and validate their effectiveness in pre-clinical models, they will be able to justify full-scale drug development with extension to human clinical trials.
Alpha-1 antitrypsin deficiency liver disease (alpha-1) is an inherited condition that affects infants, children, and adults. In those with the disease, the abnormal alpha-1 antitrypsin (A1AT) protein accumulates in the liver instead of being secreted or broken down. Over time, that accumulation causes liver damage and scarring, and alpha-1 is the most common genetic reason that children undergo liver transplantation. However, only a subset of alpha-1 patients develops serious liver disease. Thus, other factors must influence disease risk. Currently, there is no way to predict which alpha-1 patients are at risk of developing liver disease or to prevent or reverse such development. Recent analyses show that genetic disruption of insulin signaling reduces abnormal A1AT accumulation in both worm and mouse models of alpha-1. With funding from the CDI, David Rudnick, MD, PhD, pediatrics; and Stephen Pak, PhD, will test drugs that disrupt insulin signaling targets to identify novel candidate therapies for alpha-1 liver disease.
Recent Zika virus (ZIKV) outbreaks have drawn attention for the virus’ ability to impede brain development. Using mouse models, Jonathan Miner, PhD, medicine; Robyn Klein, MD, PhD, medicine, neuroscience; and Joseph Culver, PhD, radiology, will pursue a CDI-funded study to define the long-term effects of ZIKV and other congenital infections on learning and memory. In a study that could have direct implications for pediatric disease, especially for ZIKV infection in children, the researchers will use optical tomography to determine the virus’ effects on the brain. Their findings could lead to therapies for this life-limiting infectious disease.
Addressing Devastating Gastrointestinal Illnesses Affecting Children
Also in this group of funded projects are three investigations that aim to learn more about the biological processes that lead to necrotizing enterocolitis (NEC) in premature infants and one aimed at setting up a system to test a treatment for short gut syndrome that can follow surgery for NEC or other serious gastrointestinal conditions. The high-level of interest in NEC is for good reason. NEC is the leading cause of death for premature infants after the second week of life, and so far, no preventive strategies have reduced the rate of NEC. The most prominent feature of this disease is the destruction of intestinal tissue, which is why an infant who somehow survives NEC will require tube feeding, which puts the kidneys at risk.
· With funding through her CDI Faculty Scholar Award, Misty Good, MD, MS, pediatrics, will work to identify the mechanisms in the gastrointestinal tract of premature babies that identify babies at the highest risk for NEC. Using mouse models, Dr. Good wants to determine the components of breast milk that are protective against NEC, gain a better understanding of how NEC develops in order to thwart its development before damage in these fragile infants is done.
· Recent data suggest that a microbial imbalance — too much bad bacteria and not enough good — precedes the onset of NEC. Brigida Rusconi, PhD, a postdoctoral fellow at the School of Medicine, will use her new CDI fellowship award to follow up on an untargeted metabolic analysis that revealed the presence of a family of host lipids made by tgastrointenstial tract just prior to NEC onset. Dr. Rusconi’s study will define the role that these lipids play in NEC-related gut injury. Her findings could be used to identify at-risk babies to provide targeted care and prevention of this devastating disorder.
· The process of discovery for complex conditions, such as necrotizing enterocolitis, inflammatory bowel disease, and short gut syndrome (SGS), is slower when experimental models omit key aspects of human biology. Kristen Seiler, MD, surgery, will use her CDI fellowship award to address this problem. In collaboration with Washington University biomedical engineers, Dr. Seiler will leverage bioengineered “organ-on-a-chip” microfluidic technology to develop a three-dimensional model that approximates small intestine physiology. Using this novel system, Dr. Seiler will explore a promising regenerative medicine treatment strategy SGS. This will lead new, targeted therapies for children suffering from SGS and other gastrointestinal illnesses.
· In a multidisciplinary approach combining cell biology, animal models and drug discovery, Stephen Pak, PhD, pediatrics; and Clifford Luke, PhD, pediatrics, will use their CDI award to screen novel compounds for their ability to stop the death of intestinal tissue, the hallmark of NEC. They will leverage their previous success at creating a model of intestinal tissue death in round worms (Caenorhabditis elegans) to keep the cost of pilot drug screens low and the pace of discovery high.
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The Children's Discovery Institute, a partnership between St. Louis Children's Hospital
and Washington University School of Medicine, will accelerate cures for the most
life-threatening diseases of childhood through collaborative and interdisciplinary