PHILADELPHIA — Researchers are closer to finding a better way to treat children with a rare metabolic disorder called MPS I. It is caused by a deficiency of the key enzyme IDUA needed to break down complex sugars in cells. MPS I eventually leads to the abnormal accumulation of sugar debris and cell death. The two main treatments are bone marrow transplantation and intravenous enzyme replacement therapy; however, both are only marginally effective or clinically impractical, especially when the disease enters the central nervous system (CNS).

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In an ongoing preclinical program using gene therapy to help cells restore normal levels of IDUA, researchers from the Perelman School of Medicine at the University of Pennsylvania have shown that exposure to the human IDUA protein early in the life of an MPS I canine model increased immune tolerance to the foreign gene. Normally the dogs elicit a strong immune response to the human IDUA protein, making it difficult to test whether gene therapy is effective. The team published their findings this month in Molecular Genetics and Metabolism.

In the dogs that were exposed to the human IDUA protein early in life, the gene therapy could be tested without interference from an immune response. When the gene was delivered to the brain in these immune-tolerant dogs, the researchers observed widespread expression of the enzyme and resolution of the brain lesions that typically occur in MPS I patients.

“Our approach can test new human gene therapies in relevant animal models and may also have clinical applications for the prevention of immune responses to gene and protein replacement therapies,” said first author Christian Hinderer, PhD, a senior research investigator working to complete his medical degree in the MD-PhD program at Penn. Hinderer, senior author James M. Wilson, MD, PhD, a professor of Medicine and Pediatrics and director of the Penn Orphan Disease Center, and Penn coauthor Mark Haskin, PhD, VMD, worked with Plott hounds, in which MPS I naturally occurs. These dogs were originally used to develop Aldurazyme, a substance used in enzyme replacement therapy that breaks down the protein fragments left in cells.

MPS I is part of a family of 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 individual MPS disorders share symptoms, such as vision 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, but individuals with the most severe form rarely live more than 10 years.

MPS I dogs have similar CNS, heart, and brain features as humans with MPS I. The dog model is better than mouse models for delivering the IDUA gene to the brain because the canine brain is closer in size to humans and better recapitulates human disease.

Animal models that closely mimic human disease are essential for preclinical evaluation of gene and protein therapeutics. However, these studies can be complicated by exaggerated immune responses against the human genes. In this paper, the team demonstrated that dogs with a genetic deficiency of IDUA were rendered immunologically tolerant to human IDUA through early exposure to the enzyme.

The team used an adeno-associated viral (AAV) vector to introduce normal human IDUA to glial and neuronal cells of the brain and spinal cord in dogs. Their aim was to treat the CNS manifestations of MPS I at the source. After a single injection of the AAV9 vector expressing a human IDUA gene sequence into the spinal fluid, they saw enzyme expression exceeding normal levels in spinal fluid, and complete reversal of the characteristic brain lesions of MPS I.

These studies may help inform the planning and design of first-in-human trials.REGENXBIO Inc., which has exclusively licensed certain key AAV-related technologies from Penn,is involved in planning studies to test treatments for MPS I.

This work was supported by a grant from REGENXBIO and the National Institutes of Health (P40-OD010939, DK54481).

Co-authors include Peter Bell, Nathan Katz, Yanqing Zhu, Gloria Lin, Ruth Choa,
Jessica Bagel, Patricia O'Donnell, Caitlin A. Fitzgerald, Therese Langan, Ping Wang, Margret L. Casal, and Mark E. Haskins, all from Penn.

Editor’s Note: Wilson is an advisor to REGENXBIO and is a founder of, holds equity in, and has a sponsored research agreement with REGENXBIO.

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PHILADELPHIA – E. John Wherry, PhD, a professor of Microbiology, director of the Institute for Immunology, and co-director of the Parker Institute for Cancer Immunotherapy at the Perelman School of Medicine at the University of Pennsylvania, has been awarded the 2016 Frederick W. Alt Award for New Discoveries in Immunology from the Cancer Research Institute (CRI).

E. John Wherry, PhD

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The award honors an outstanding former CRI-Irvington postdoctoral fellow and is named after former fellow Frederick W. Alt, MD, a professor of Genetics at Harvard Medical School. The fellowship, established in 1971, is CRI’s longest-standing program. Fellowships provide support to fund and train young immunologists around the world. Wherry was a CRI-Irvington postdoctoral fellow from 2000 to 2003 at Emory University.

Wherry’s discoveries include insights into how changes in gene expression affect T cell exhaustion, which is a loss of immune function that occurs as a result of chronic viral infection and cancer. Normally, during a short-term infection, such as the flu, immune cells handily eliminate the offending pathogen. But in the long-term, chronic infections such as hepatitis C, HIV, and malaria, and also in cancer, T cells and the opposing pathogen or malignancy engage in a continuous struggle, and over time the T cells become “exhausted,” giving cancer or the pathogen the edge.

Several current immunotherapies for human cancer work in part by reversing T cell exhaustion.

Wherry received his bachelor’s degree in science from the Pennsylvania State University in 1993 and his doctorate in immunology from Thomas Jefferson University in 2000. He has been recognized as one of the most frequently cited researchers in his field by Thomson/ISI and named one of America’s Young Innovators by Smithsonian magazine (2007). He serves on many scientific advisory panels and editorial boards, including the Journal of Experimental Medicine, PLoS Pathogens, Cancer Immunology Research, the Journal of Immunology, and the Journal of Leukocyte Biology.

The Cancer Research Institute, which was established in 1953, supports immune system-based strategies to prevent, diagnose, treat, and eventually cure all cancers. An award ceremony, which will include other award presentations, will take place at the Cancer Research Institute’s 30th Annual Awards Dinner on September 27, 2016 in New York City.

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PHILADELPHIA – Martin G. St. John Sutton, MBBS, FRCP, a John Bryfogle emeritus professor of Cardiovascular Medicine in the Perelman School of Medicine at the University of Pennsylvania, has received the 2016 Lifetime Achievement Award from the American Society of Echocardiography (ASE) for his pioneering contributions to structural and functional ventricular remodeling and repair.

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The ASE Lifetime Achievement Awards recognizes a physician who has had a lifetime of outstanding achievements in the field of cardiovascular ultrasound and who has served as a role model through service, research and teaching. Those who receive this award have had a career in cardiovascular ultrasound for at least 25 years, and are recognized at local, national and international levels. St. John Sutton accepted the award in Seattle in June.

“Martin’s work codified the tools we now commonly use to quantify changes in size, shape, and function of the heart under many conditions, which has become the foundation for all subsequent studies of ventricular remodeling,” said Victor A. Ferrari, MD, a professor of Cardiovascular Medicine. “His studies of reverse – or beneficial – remodeling using Cardiac Resynchronization Therapy were groundbreaking, and led the field in a completely new direction. Martin is not only a great friend and colleague, but as director of the Cardiovascular Fellowship program, he set the bar for education in the field, having developed one of the most sought after training programs in the country.”

St. John Sutton has been a fellow of the ASE since 2004, and a member of the ASE Writing Group for Quantitation of Ventricular Function Task Force for nearly 20 years; in addition, he is involved with numerous national and international cardiovascular and medical organizations.

In addition to the Cardiovascular Fellowship program, St. John Sutton directed Penn’s Cardiovascular Imaging Division from 1993 to 2014 and the Center for Quantitative Echocardiography for 20 years. In this role, he led imaging analyses for many large randomized, multi-center trials, which have been fundamental to the understanding of cardiac remodeling in heart failure, and have revolutionized both drug and device therapy in cardiovascular medicine. Over the course of his career, St. John Sutton also co-authored more than 320 peer-reviewed publications in heart failure, congenital heart disease, and echocardiography.

“Martin is one the greatest teachers and physicians I have had the privilege of working with,” said Bonnie Ky, MD, MSCE, an assistant professor of Cardiovascular Medicine. “He has had a seminal impact on the field’s understanding of cardiac remodeling in heart failure, and has played a critical role in shaping not only my own academic career, but the careers of countless others.”

St. John Sutton earned his bachelor’s degree and medicine degree from Guys Hospital Medical School in London, UK. He first joined the Perelman School of Medicine at the University of Pennsylvania faculty as an instructor in Medicine in 1979, before becoming an assistant professor of Medicine in 1980. St. John Sutton held faculty positions and directed the Echocardiography Laboratories at the Brigham and Women’s Hospital in Boston and the Royal Brompton Hospital in London from 1984 through 1993, and was also recognized as a Fellow of the Royal College of Physicians in 1993. He returned to Penn as the John W. Bryfogle Professor of Medicine that same year, and became an emeritus professor in 2014.

“Martin is a pioneer, a wonderful colleague and a generous mentor who has trained many of nation’s leading cardiologists,” said Thomas Cappola, MD, ScM, chief of the Division of Cardiovascular Medicine. “We are thrilled that he has received the ASE lifetime achievement award, it is certainly well-deserved.”

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PHILADELPHIA — Two Penn Medicine researchers have received $3.1 million in research funding contracts from the Patient-Centered Outcomes Research Institute (PCORI) to develop tools that will help patients understand the addiction risks associated with opioid prescription drugs, and allow researchers to harness data from electronic health records (EHR) to better predict disease patterns. PCORI is an independent, nonprofit organization that funds research intended to provide patients, their caregivers, and clinicians with the evidence-based information needed to make better-informed healthcare decisions.

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Amid a devastating public health crisis, in which 19,000 overdose deaths per year in the United States are due to prescription opioids, Zachary Meisel, MD, an assistant professor of Emergency Medicine, aims to use his three-year, $2.1 million award to conduct the first large-scale multi-center randomized clinical trial aimed at improving communication between physicians and patients with acute pain in order to improve education about individual risks of opioid misuse. The trial, which will enroll 1,100 patients who are set to discharge from acute care settings after being treated for acute back or acute kidney stone pain, will compare the effectiveness of different tools used to inform patients about pain management strategies, opioid use and addiction risk. Tools might include fact sheets, video narrative vignettes, interactive questions, and a pain scoring system that will allow patients to calculate their own level of addiction risk.

Health care providers, Meisel says, need more effective ways to understand their patients’ pain, and patients need tools that will help them better understand the risks associated with opioid prescriptions and more accurately communicate with care providers about their preferences for pain management.

“Patients with kidney stones, back pain, or pain resulting from other acute conditions, may benefit from opioids, but also respond to non-opioid alternatives. We also know that these powerful and addictive medications are being over prescribed, perhaps in part because of a lack of education and communication on both sides of the conversation,” Meisel said. “Conversations between physicians and patients will always be of the utmost importance, but having easy to use tools will help patients understand their risks and also inform physicians about best practices with opioid prescribing, will ultimately help tackle what is now widely recognized as a national epidemic.”

In a second PCORI grant, Rebecca A. Hubbard, PhD, an associate professor of biostatistics in Biostatistics and Epidemiology, and colleagues will undertake a three-year $1 million grant to support creation of new statistical techniques and software to estimate latent, or hidden phenotypes – the observable characteristics including health conditions that describe an individual – using data from electronic health records (EHR). The objective of these methods is to yield new insights into the association between phenotypes and health outcomes using messy and incomplete data from EHR.

As an example of the use of these new methods, Hubbard and her team will study EHR for children and adolescents to attempt to identify individuals with type II diabetes before a clinical diagnosis has been made. Using EHR data from eight children’s hospital health systems participating in the PEDSnet federation, they will develop a pediatric diabetes latent phenotype using the unique set of measures available for each individual patient. This phenotype can be used in research to assess an individual’s risk of specific health outcomes and offers insight into a person’s true disease profile that may otherwise be only hinted at by the measurements available in a patient’s EHR.

“Electronic health records can provide rich data on an individual’s health and disease risk factors but the incomplete and inconsistent nature of the information available across patients makes it difficult to discern a pattern,” said Hubbard. “By creating these statistical methods, we’re pooling relevant data in a new way that can more accurately and precisely pinpoint an individual’s disease profile. In doing so, we can advance research and support improved patient care.”

Co-investigators on Hubbard’s study are Penn colleagues Yong Chen, PhD, and Jinbo Chen, PhD, as well as L. Charles Bailey, MD, from Penn and the Children’s Hospital of Philadelphia. More information on this project is available on the PCORI site.

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INDIANAPOLIS – When the body encounters an infection, a molecular signaling system ramps up the body's infection-fighting system to produce more white blood cells to attack invading bacteria. Now researchers have discovered that when facing a massive bacterial infection resulting in sepsis, that same signaling system malfunctions, damaging the body's ability to fight the invaders.

In addition to suppressing the mature blood cells battling against the infection, malfunctioning of this signaling system results in permanent damage to the body's blood producing cells – called hematopoietic stem cells – that are located in the bone marrow. The research, by scientists at the Indiana University School of Medicine, was published recently in the journal Stem Cell Reports.

Sepsis is a life-threatening response by the body's inflammatory system that can result from severe bacterial infections. It is a growing problem: The number of hospitalizations for sepsis more than doubled from 2000 to 2008, reaching more than 1.1 million, according to the Centers for Disease Control and Prevention. Patients with severe sepsis or septic shock have a mortality (death) rate of about 40%-60%, with the elderly having the highest death rates. Newborns and pediatric patients with sepsis have about a 9%-36% mortality rate.

"Our goal is to find out what causes this bone marrow failure during serious infections, and find ways to prevent it," said Nadia Carlesso, M.D., Ph.D., professor of pediatrics and of medical and molecular genetics at the IU School of Medicine.

Most research has focused on understanding and managing the late consequences of sepsis while little is known about the changes occurring in the bone marrow at early stages of the response to bacterial infection, when the opportunity for effective treatment might still be available. Dr. Carlesso’s group has pioneered the study of bone marrow responses during acute infection. Using laboratory models of severe sepsis her group has discovered that the blood-producing stem cells fail to continuously generate mature neutrophils, which are the most critical bacteria-fighting cells.

"In this research we determined that in cases of severe infection and sepsis, a key mechanism in the body's response to infection is broken. These findings point to potential new targets for protecting the immune system during major infections," Dr. Carlesso said.

The IU researchers focused on a set of proteins called toll-like receptors, which function as sentinels on the surfaces of cells. When the receptors detect the presence of invading bacteria, they send signals to the body's immune response system. The IU researchers looked at toll receptor 4 (TLR4), which activates two signaling pathways that stimulate the production of more neutrophils during common infections, but suppress it during severe infections.

In a laboratory model of sepsis using mice, the researchers found that two abnormal effects activated by toll receptor 4 during severe infection — the suppression of neutrophil production and the damage to the bone marrow's blood-producing stem cells — are mediated by two different molecules downstream of TLR4.

"This study is a good start, as provides a more precise map to follow, but more research is needed to better understand this process and develop better, and much needed, therapeutic strategies for sepsis," said Dr. Carlesso.

The research was supported by grants from the National Institutes of Health (R01 HL068256-05, R01 DK097837-09 and R01 HL124159-01, the MPN Research Foundation, Ralph W. and Grace M. Showalter Research Trust Fund, the American Heart Association and the National Institute of Diabetes and Digestive and Kidney Diseases Center of Excellence in Molecular Hematology.

In addition to Dr. Carlesso, investigators contributing to this research were Huajia Zhang, Sonia Rodriguez, Lin Wang, Soujuan Wang, Henrique Serezani, Reuben Kapur and Angelo A. Cardoso.

Drs. Carlesso and Kapur are members of the Herman B Wells Center for Pediatric Research. Drs. Carlesso, Cardoso, Kapur and Serezani are members of the Indiana University Melvin and Bren Simon Cancer Center.

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