ABIGAIL WEXNER RESEARCH INSTITUTE

Department, Section and Center Reports

John A. Barnard, MD

President

Dennis R. Durbin, MD, MSCE

Chief Scientific Officer

ABIGAIL WEXNER RESEARCH INSTITUTE AT NATIONWIDE CHILDREN’S HOSPITAL

As an international leader in pediatric research, science is thriving at Nationwide Children’s. The behavioral, basic and clinician scientists within the Abigail Wexner Research Institute (AWRI) at Nationwide Children’s are redefining pediatric health care with best outcomes for every child in mind. The AWRI occupies more than 500,000 square feet of dedicated research space on the Nationwide Children’s campus. One of the largest pediatric research centers in the United States, the AWRI is ranked in the top six for National Institutes of Health funding among free-standing children’s hospitals. The centers of emphasis are structured to support multidisciplinary team science and discovery, enabled by outstanding shared resources. Each center is home to faculty members working in contiguous space and collaborating with talented staff, postdoctoral fellows, graduate students, residents and other students.

INSTITUTE LEADERSHIP

Lauren O. Bakaletz, PhD

Vice President, Basic Sciences Research

William E. Smoyer, MD

Vice President, Clinical Research

Deena J. Chisolm, PhD

Vice President, Health Services Research

Veronica J. Vieland, PhD

Vice President, Computational Research

INSTITUTES AND CENTERS OF EMPHASIS

• Battelle Center for

Mathematical Medicine • Biopathology Center • Center for

Biobehavioral Health • Center for

Cardiovascular Research • Center for Childhood

Cancer and Blood Diseases • Center for Clinical and

Translational Research • Center for Gene Therapy • Center for Injury

Research and Policy • Center for Innovation in Pediatric Practice • Center for Microbial

Pathogenesis • Center for Perinatal Research • Center for Regenerative

Medicine • Center for Vaccines and Immunity • Steve and Cindy Rasmussen

Institute for Genomic

Medicine

Research Institute Reports

BATTELLE CENTER FOR MATHEMATICAL MEDICINE

Faculty from the Battelle Center for Mathematical Medicine in the Abigail Wexner Research Institute at Nationwide Children’s Hospital apply state-of-the-art, quantitative methods to basic and clinical research in order to better inform and ultimately improve clinical care in pediatrics. A primary goal of the center is to provide a unique environment in which specialists from a variety of mathematical, statistical and computational areas can share their professional “home” in order to facilitate creative, collaborative research within the group.

FACULTY

Veronica J. Vieland, PhD

Director

Christopher W. Bartlett, PhD Jayajit Das, PhD David A. Greenberg, PhD Andrzej Kloczkowski, PhD Paola Malerba, PhD William C. Ray, PhD William Stewart, PhD

Battelle Center for Mathematical Medicine faculty continued their tradition of active collaboration with one another, with investigators across the Nationwide Children’s organization and with colleagues at The Ohio State University and other institutions. This year saw the publication of 19 peer-reviewed research papers and the filing of one patent, the awarding of several new research grants and the presentation of 16 invited research talks at high-profile national and international venues spanning seven countries. Our faculty also participated in organizing five national and international conferences on several topics in computational biology.

GRANTS AWARDED JULY 1, 2019 – JUNE 30, 2020

$1,595,941

SELECTED PUBLICATIONS

Álvarez-Machancoses Ó, De Andrés-Galiana EJ, Fernández-Martínez JL, Kloczkowski A. Robust Prediction of Single and Multiple Point Protein Mutations Stability Changes. Biomolecules. 2019 Dec 31;10(1):67.

Bartlett CW, Klamer BG, Buyske S, Petrill SA, Ray WC. Forming Big Datasets through Latent Class Concatenation of Imperfectly Matched Databases Features. Genes (Basel). 2019 Sep 19;10(9):727.

Komarov M, Malerba P, Golden R, Nunez P, Halgren E, Bazhenov M. Selective recruitment of cortical neurons by electrical stimulation. PLoS Computational Biology. 2019 Aug 26;15(8):e1007277.

Pathak S, Stewart WCL, Burd CE, Hester ME, Greenberg DA. Brd2 haploinsufficiency extends lifespan and healthspan in C57B6/J mice. PLoS One. 2020 Jun 19;15(6):e0234910.

Wethington D, Harder O, Uppulury K, Stewart WCL, Chen P, King T, Reynolds SD, Perelson A, Peeples ME, Niewiesk S, Das J. Mathematical modelling identifies the role of adaptive immunity as a key controller of respiratory syncytial virus in cotton rats. Journal of the Royal Society, Interface. 2019 Nov 29;16(160):20190389.

Research Institute Reports

BIOPATHOLOGY CENTER

The Biopathology Center provides a full range of services related to biospecimen procurement, banking, processing, testing and distribution. The Biopathology Center is accredited by the College of American Pathologists Biorepository Accreditation Program (CAP BAP) and houses numerous National Cancer Institute (NCI) funded biospecimen collection efforts, including the biorepositories of the Children’s Oncology Group (COG) and SWOG. Also part of the Biopathology Center are the NCI-funded Pediatric Division of the Cooperative Human Tissue Network and the Biospecimen Core Resource of the Center for Cancer Genomics (CCG BCR), as well as numerous biospecimen collections from other sponsors (e.g., Nationwide Children’s-funded investigators, the SARC Foundation).

FACULTY

Nilsa Del Carmen Ramirez-Milan, MD, FCAP

Medical Director and Principal Investigator

Jay Bowen, MS

Principal Investigator

Kathleen Nicol, MD, FCAP

Principal Investigator We continuously pursue grant-supported, biorepositorybased studies aimed to advance medical research. The Biopathology Center was awarded three NCI-sponsored U24 grants for the period of 2020 to 2026: two for supporting the ongoing biobanking efforts of COG and SWOG and a new one to support the Early-Phase and Experimental Clinical Trials (EET) Biobank. Also awarded was funding to support the NRG Oncology-Columbus biobank. The COG, SWOG and NRG OncologyColumbus biobanks are part of the NCI-sponsored National Clinical Trials Network and support large phase 2 and phase 3 clinical trials; the EET Biobank supports phase 1 clinical trials.

The CCG BCR was awarded contracts to support pathology review and nucleic acid isolation for the NCI Division of Cancer Epidemiology and Genetics (to study environmental causes of cancer), the Clinical Trial Sequencing Project (to analyze cancer genomes from the ECOG-ACRIN 2805 renal cancer trial), Early Onset Malignancies Initiative (to investigate why certain racial and ethnic populations are at increased risk of developing cancer at an early age) and the Human Cancer Model Initiative (an international consortium generating novel, next-generation, tumor-derived culture models annotated with genomic and clinical data).

Mr. Bowen replaced Dr. Gastier-Foster as PI of the Biospecimen Core Resource of the Center for Cancer Genomics in October 2019. In June 2020 he and Dr. Gastier-Foster were recipients of the American Association for Cancer Research (AACR) Team Science Award: The Cancer Genome Atlas. Dr. Nicol is contact-PI of the EET Biobank. Dr. Ramirez-Milan is contact-PI of the COG and SWOG biobanks and PI of the NRG OncologyColumbus and EET biobanks. Last September, she received a CAP Lifetime Achievement Award for her contributions to the field of pathology and her efforts to establish their Biorepository Accreditation Program.

GRANTS AWARDED JULY 1, 2019 – JUNE 30, 2020

$18,887,897

SELECTED PUBLICATIONS

Conley BA, Staudt L, Takebe N, Wheeler DA, Wang L, Cardenas MF, Zenklusen JC, McShane LM, Tricoli JV, Williams PM, Lubensky I, O’Sullivan-Coyne G, Kohn E, Little R, White J, Malik S, Harris LN, Mann B, Weil C, Tarnuzzer R, Karlovich C, Rodgers B, Shankar L, Jacobs PM, Nolan T, Gastier-Foster J, Bowen J, Leraas K, Shen H, Laird PW, Esteller M, Miller V, Johnson A, Edmondson EF, Ivy SP. The Exceptional Responders Initiative: Feasibility of a National Cancer Institute Pilot Study. Journal of the National Cancer Institute. 2020 Apr 27;djaa061. [Epub ahead of print]

Makhlouf H, Watson MA, Lankes HA, Weil C, Dickler M, Birrer M, Moskaluk C, Ramirez NC, Okby N, Alonsozana E, Barnes M, Goldman EB, Enos R, Lubensky I. Toward Improving Practices for Submission of Diagnostic Tissue Blocks for National Cancer Institute Clinical Trials. American Journal of Clinical Pathology. 2020 Jan 2;153(2):149-155.

Ponnapalli SP, Bradley MW, Devine K, Bowen J, Coppens SE, Leraas KM, Milash BA, Li F, Luo H, Qiu S, Wu K, Yang H, Wittwer CT, Palmer CA, Jensen RL, Gastier-Foster JM, Hanson HA, Barnholtz-Sloan JS, Alter O. Retrospective clinical trial experimentally validates glioblastoma genome-wide pattern of DNA copy-number alterations predictor of survival. APL Bioengineering, 2020 Apr;4(2):026106.

Rokita JL, Rathi KS, Cardenas MF, Upton KA, Jayaseelan J, Cross KL, Pfeil J, Egolf LE, Way GP, Farrel A, Kendsersky NM, Patel K, Gaonkar KS, Modi A, Berko ER, Lopez G, Vaksman Z, Mayoh C, Nance J, Mccoy K, Haber M, Evans K, McCalmont H, Bendak K, Böhm JW, Marshall GM, Tyrrell V, Kalletla K, Braun FK, Qi L, Du Y, Zhang H, Lindsay HB, Zhao S, Shu J, Baxter P, Morton C, Kurmashev D, Zheng S, Chen Y, Bowen J, Bryan AC, Leraas KM, Coppens SE, Doddapaneni H, Momin Z, Zhang W, Sacks GI, Hart LS, Krytska K, Mosse YP, Gatto GJ, Sanchez Y, Greene CS, Diskin SJ, Vaske OM, Haussler D, Gastier-Foster JM, Kolb EA, Gorlick R, Li X-N, Reynolds CP, Kurmasheva RT, Houghton PJ, Smith MA, Lock RB, Raman P, Wheeler DA. Genomic profiling of childhood tumor patient-derived xenograft models to enable rational clinical trial design. Cell Reports. 2019 Nov 5;29(6):1675-1689.e9.

Research Institute Reports

CENTER FOR BIOBEHAVIORAL HEALTH

The mission of the Center for Biobehavioral Health in the Abigail Wexner Research Institute at Nationwide Children’s Hospital is to improve the health and health care of children and their families. This is achieved through state-of-the-art research using a biopsychosocial approach. A special focus is placed on identification of factors associated with developmental risk and resilience across the life span, design and evaluation of new interventions, and dissemination and implementation of effective interventions into routine practice.

FACULTY

Cynthia A. Gerhardt, PhD

Director

FULL-TIME NATIONWIDE CHILDREN’S FACULTY

Canice E. Crerand, PhD Kristen E. Hoskinson, PhD Jamie L. Jackson, PhD Sarah A. Keim, PhD Laura Mackner, PhD Leena Nahata, MD Eric E. Nelson, PhD Joseph R. Rausch, PhD Jack H. Stevens, PhD H. Gerry Taylor, PhD Kathryn A. Vannatta, PhD

OSU-AFFILIATE FACULTY

Christine A. Fortney, PhD, RN Tondi Harrison, PhD, RN Kathy Lemanek, PhD Kelly McNally, PhD Our vision is to achieve the best possible outcomes for children and families by creating, disseminating and applying new knowledge related to the reciprocal influences of behavior and health. We are also committed to training the next generation of leaders in biobehavioral research. Developmental, behavioral and social risk factors contribute to significant morbidity and mortality among youth. Childhood health conditions affect not only the psychosocial well-being of youth but also that of families. Through our research, the center is transforming the health care and well-being of children and families in our community and worldwide. Several new grants were awarded in the center. Kathryn Vannatta, PhD, received a four-year, $2.29 million grant from the National Heart, Lung and Blood Institute (NHLBI). The study team will examine the developmental progression of youth with critical congenital heart defects, particularly the role of social cognition in peer relationships across elementary and middle school. The goal is to also identify family and environmental factors that may protect against difficulties for these children. Jamie Jackson, PhD, was awarded a pilot grant from NHLBI to adapt a physical activity intervention for young adults with congenital heart disease (CHD). The goal is to improve health outcomes among the growing population of CHD survivors as these youth mature into adulthood. H. Gerry Taylor, PhD, became the founding director of the Neurodevelopmental Research Affinity Group (NRAG), which now includes over 60 investigators across Nationwide Children’s and OSU. The NRAG provides pilot funding and fosters collaboration on neurodevelopmental studies across the institutions. Kristen Hoskinson, PhD, was named the 2019 Department of Pediatrics Outstanding Junior Faculty Investigator for her research in the field of pediatric neuropsychology, particularly social outcomes in youth with traumatic brain injuries. Behavioral Health: See page 132 for information about Behavioral Health services at Nationwide Children’s Hospital.

GRANTS AWARDED JULY 1, 2019 – JUNE 30, 2020

$2,638,242

SELECTED PUBLICATIONS

Crerand CE, Rumsey N, Kazak AE, Clark A, Rausch J, Sarwer DB. Sex differences in perceived stigmatization, body image disturbance, and satisfaction with facial appearance and speech among adolescents with craniofacial conditions. Body Image. 2020 Mar;32:190-198.

Grupp-Phelan J, Stevens J, Boyd S, Cohen DM, Ammerman RT, Liddy-Hicks S, Heck K, Marcus SC, Stone L, Campo JV, Bridge JA. Effect of a motivational interviewing–based intervention on initiation of mental health treatment and mental health after an emergency department visit among suicidal adolescents: A randomized clinical trial. JAMA network open. 2019 Dec 2;2(12):e1917941-.

Hoskinson KE, Bigler ED, Abildskov TJ, Dennis M, Taylor HG, Rubin K, Gerhardt CA, Vannatta K, Stancin T, & Yeates KO. (2019). The mentalizing network and theory of mind mediate adjustment after childhood traumatic brain injury. Social Cognitive and Affective Neuroscience. 2019 Dec 14;(12):1285-1295.

Nahata L, Chen D, Quinn GP, Travis M, Grannis C, Nelson E, Tishelman AC. Reproductive attitudes and behaviors among transgender/nonbinary adolescents. Journal of Adolescent Health. 2020 Mar 1;66(3):372-4.

Research Institute Reports

CENTER FOR CARDIOVASCULAR RESEARCH

The mission of the Center for Cardiovascular Research in the Abigail Wexner Research Institute at Nationwide Children’s Hospital is to conduct innovative, mechanism-based research leading to improved therapies and outcomes for pediatric cardiovascular diseases and to foster preventive strategies and promote cardiovascular health in adults.

FACULTY

Vidu Garg, MD

Director

Madhumita Basu, PhD

Brenda Lilly, PhD Kim L. McBride, MD, MS

Patrick I. McConnell, MD

Aaron J. Trask, PhD

Mingtao Zhao, DVM, PhD

Our cardiovascular research projects span the spectrum from basic research, which occurs in the Center for Cardiovascular Research, to translational and clinical research that is performed in collaboration with clinicians in The Heart Center at Nationwide Children’s. Areas of focus include investigation into the genes and geneenvironment interactions that contribute to congenital heart defects, molecular and signaling pathways regulating normal heart and blood vessel development and how they are disrupted during disease development and progression. The center faculty receive funding from the National Institutes of Health (NIH) and the American Heart Association (AHA) to support their cutting-edge research. In the past year, Dr. Mingtao Zhao joined our center and brought expertise in stem cell biology to the center. Drs. Zhao, McBride and Garg along with other faculty in The Heart Center were awarded funding from the Additional Ventures Innovation Fund to study genetic and molecular aspects of single ventricle heart disease. Additionally, faculty members are investigating how the SARS-CoV-2 virus causes the heart damage observed in COVID-19 patients in collaboration with faculty in the Center for Vaccines and Immunity. Lastly, the center continues to support the cardiovascular research education of trainees at all levels. These efforts have been supported by an NIHfunded T32 postdoctoral training grant, along with an American Heart Association training award that supports summer research fellowships for undergraduate students. The Heart Center: See page 40 for information about Cardiology and page 139 for Cardiovascular Surgery services.

GRANTS AWARDED TO HEART CENTER AND CARDIOVASCULAR RESEARCH FACULTY JULY 1, 2019 – JUNE 30, 2020

$2,302,971

SELECTED PUBLICATIONS

Majumdar U, Yasuhara J, Garg V. In vivo and in vitro genetic models of congenital heart disease. Cold Spring Harbor Perspectives in Biology. 2019 Dec 9;a036764.

Manivannan SN, Darouich S, Masmoudi A, Gordon D, Zender G, Han Z, FitzgeraldButt S, White P, McBride KL, Kharrat M, Garg V. Novel frameshift variant in myl2 reveals molecular differences between dominant and recessive forms of hypertrophic cardiomyopathy. PLoS Genetics. 2020 May;16(5):e1008639.

McCallinhart PE, Biwer LA, Clark OE, Isakson BE, Lilly B, Trask AJ. Myoendothelial junctions of mature coronary vessels express notch signaling proteins. Frontiers in Physiology. 2020 Feb 4;11:29.

McCallinhart PE, Cho Y, Sun Z, Ghadiali S, Meininger GA, Trask AJ. Reduced stiffness and augmented traction force in type 2 diabetic coronary microvascular smooth muscle. American Journal of Physiology-Heart and Circulatory Physiology. 2020 Jun 1;318(6):H1410-H1419.

Zhao MT, Shao NY, Garg V. Subtype-specific cardiomyocytes for precision medicine: Where are we now? Stem Cells. 2020 Mar 30. [Epub ahead of print]

Research Institute Reports

CENTER FOR CHILDHOOD CANCER AND BLOOD DISEASES

The mission of the Center for Childhood Cancer and Blood Diseases in the Abigail Wexner Research Institute at Nationwide Children’s Hospital is to transform the care of children, adolescents and young adults with cancer and blood diseases through research and clinical translation. Center investigators collaborate closely to study how cells grow, divide and function, how these basic processes are usurped to allow cancers to develop, how the body responds to developing cancers and how this knowledge can be used to better diagnose and treat these diseases. Investigators work closely with physicians at Nationwide Children’s, as well as with national and international colleagues, to translate these findings to the patient.

FACULTY

Stephen L. Lessnick, MD, PhD

Director Kevin A. Cassady, MD Dawn S. Chandler, PhD Long-Sheng Chang, PhD Timothy P. Cripe, MD, PhD Genevieve C. Kendall, PhD Dean A. Lee, MD, PhD Jeffrey R. Leonard, MD Ryan D. Roberts, MD, PhD Benjamin Z. Stanton, PhD Emily R. Theisen, PhD Ruoning Wang, PhD

Genevieve Kendall, PhD, and Emily Theisen, PhD, are new investigators in the Center for Childhood Cancer and Blood Diseases. Dr. Kendall’s research focuses on how single gene mutations (called translocations, such as PAX3/FOXO) can cause sarcomas (such as alveolar rhabdomyosarcoma) in children. Dr. Kendall uses zebrafish as her primary model system as this organism allows for direct observation of tumor development while also allowing for genetic manipulation to better understand how different genes work together to cause cancer. Dr. Theisen also focuses on sarcoma development and her research examines the interplay between epigenetic regulators (such as lysine specific demethylase 1, or LSD1) and cancer-causing translocations (such as EWS/FLI in Ewing sarcoma). Both of these laboratories are deeply interested in identifying therapeutic opportunities to disrupt the process of tumor development, and thereby support the development of new treatments for cancer in children. These new teams are integrated with a growing collaborative of pediatric sarcoma research programs in the center. This collaborative has been leveraged in the form of multiple large, collaborative grants (U54 awards) from the National Institutes of Health and the National Cancer Institute as part of their Cancer Moonshot Initiative. One of these U54 awards is led by Stephen Lessnick, MD, PhD, and seeks to understand how the EWS/FLI mutant protein regulates genes that cause Ewing sarcoma. The second U54 award is led by Timothy Cripe, MD, PhD, and studies various aspects of how the immune system can be manipulated to treat pediatric cancers, including sarcomas. Hematology/Oncology/BMT: See page 80 for information about the Division of Hematology, Oncology & Blood and Marrow Transplant at Nationwide Children’s Hospital.

GRANTS AWARDED TO CENTER AND DIVISION CLINICAL AND RESEARCH FACULTY JULY 1, 2019 – JUNE 30, 2020

$15,198,205

SELECTED PUBLICATIONS

Gryder BE, Khan J, Stanton BZ. Measurement of differential chromatin interactions with absolute quantification of architecture (AQuA-HiChIP). Nature Protocols. 2020 Mar;15(3):1209-1236.

Reinecke JB, Roberts RD. Targetable Intercellular Signaling Pathways Facilitate Lung Colonization in Osteosarcoma. Advances in Experimental Medicine and Biology. 2020;1258:111-123.

Showpnil, IR, Miller, KR, Taslim, CR, Pishas, K, Lessnick SL, and Theisen, ER. Mapping the structure-function relationships of disordered oncogenic transcription factors using transcriptomic analysis. Journal of Visualized Experiments. 2020 Jun 27;(160).

Wang T, Gnanaprakasam JNR, Chen X, Kang S, Xu X, Sun H, Liu L, Rodgers H, Miller E, Cassel TA, Sun Q, Vicente-Muñoz S, Warmoes MO, Lin P, Piedra-Quintero ZL, Gueraude-Arellano M, Cassady KA, Zheng SG, Yang J, Lane AN, Song X, Fan TW, Wang R. Inosine is an alternative carbon source for CD8+-T-cell function under glucose restriction. Nature Metabolism. 2020 Jul;2(7):635-647. [Epub 2020 Jun 15]

Wedekind MF, Cripe TP. Oncolytic Viruses and Their Potential as a Therapeutic Opportunity in Osteosarcoma. Advances in Experimental Medicine and Biology. 2020;1258:77-89.

Research Institute Reports

CENTER FOR CLINICAL AND TRANSLATIONAL RESEARCH

The Center for Clinical and Translational Research in the Abigail Wexner Research Institute at Nationwide Children’s Hospital is committed to improving the diagnosis, treatment and outcomes of society’s most important pediatric diseases by integrating high-caliber basic science research with innovative patient-based research.

FACULTY

William E. Smoyer, MD, FASN

Director Shipra Agrawal, PhD Carlos E. Alvarez, PhD M. Brian Becknell, MD, PhD Andrea E. Bonny, MD David R. Brigstock, PhD Christina B. Ching, MD Mitchell H. Grayson, MD Mark W. Hall, MD, FAAP, FCCM Bryce A. Kerlin, MD Kirk M. McHugh, PhD Jennifer A. Muszynski, MD Olubukola O. Nafiu, MD Lance M. Relland, MD, PhD John David Spencer, MD Eric A. Sribnick, MD, PhD Rachel M. Stanley, MD, MHSA Rajan K. Thakkar, MD The Center for Clinical and Translational Research strives to create an environment in which patients, families, researchers and clinicians all collaborate to integrate “evidence-based medicine” with “evidence-generating medicine” to ensure children benefit from the latest advances in both medical knowledge and innovative treatments to improve their health.

Our center has scientists investigating several diverse areas of research. The overarching theme of our research programs is to bring new knowledge from both bedside to bench and from bench to bedside to improve the lives of children. Our faculty are from three departments and represent nine different subspecialties: Nephrology, Hematology/Oncology, Adolescent Medicine, Critical Care, Urology, Pediatric Surgery, Anesthesia, Allergy/ Immunology and Emergency Medicine. Our research programs are very diverse and include innate immunity in urinary tract infections, immunoparalysis after sepsis or trauma, pathophysiology of stored RBC-induced immune suppression, novel treatments for nephrotic syndrome, pathophysiology of thrombosis, pathophysiology of bladder dysfunction in urinary tract obstruction, burn injury, abdominal sepsis, hepatic fibrosis, cancer genetics, adolescent addiction, interventions for traumatic brain injury, spinal cord injuries, mechanisms behind viral infection and allergic disease, perioperative respiratory complications, neonatal pain assessments and the role of pain control in immune function.

Our vision is to use the delivery of care to each pediatric patient as an opportunity to learn how to improve future care. We believe it is our responsibility to learn from every patient so that subsequent children will be able to benefit from evidence-based improved care.

Clinical Research Services is a core service provided within the Center for Clinical and Translational Research and is designed to be a portal through which clinical investigators can access streamlined coordination of services necessary to initiate clinical research projects, regardless of the funding source. Clinical Research Services supports all clinical research studies, providing staff and/or services to manage investigators’ studies according to good clinical practice and federal, state and institutional regulations and guidelines.

GRANTS AWARDED JULY 1, 2019 – JUNE 30, 2020

$7,156,998

SELECTED PUBLICATIONS

Derebail VK, Rheault MN, Kerlin BA. Role of direct oral anticoagulants in patients with kidney disease. Kidney International. 2020 Apr;97(4):664-675. Nafiu OO, Chimbira WT. Albuterol and Pediatric Perioperative Respiratory Complications. JAMA Pediatrics. 2019 Sep 16. [Epub ahead of print] Sribnick EA, Hensley J, Moore-Clingenpeel M, Muszynski JA, Thakkar RK, Hall MW. Nosocomial Infection Following Severe Traumatic Injury in Children. Pediatric Critical Care Medicine. 2020 May;21(5):443-450. Sribnick EA, Weber MD, Hall MW. Innate immune suppression after traumatic brain injury and hemorrhage in a juvenile rat model of polytrauma. Journal of Neuroimmunology. 2019 Dec 15;337:577073. Thakkar RK, Weiss SL, Fitzgerald JC, et al. Risk Factors for Mortality in Pediatric Postsurgical versus Medical Severe Sepsis. The Journal of Surgical Research. 2019 Oct;242:100-110.

Research Institute Reports

CENTER FOR GENE THERAPY

The primary mission of the Center for Gene Therapy in the Abigail Wexner Research Institute at Nationwide Children’s Hospital is to develop novel genetically based therapies for inherited diseases in order to ease the burden of these diseases on children and their families. This mission is pursued by a dedicated team of laboratory scientists whose work is directed toward clinical applications, and by the efforts of clinicianscientists who are tasked with bringing these therapies into clinical trials. To do this, the center works closely with the regulatory expert staff of Nationwide Children’s Drug and Device Development Services and the Nationwide Children’s Good Manufacturing Practice Clinical Manufacturing Facility. This integrated approach allows us to accelerate the transfer of promising therapies from the bench to the bedside.

FACULTY

Kevin M. Flanigan, MD

Director

PRINCIPAL INVESTIGATORS

Allison Bradbury, PhD Scott Harper, PhD Stephen Kaler, MD, MPH Linda Lowes, PhD Paul Martin, PhD Jerry R. Mendell, MD Kathrin Meyer, PhD Zarife Sahenk, MD Megan Waldrop, MD Nicolas Wein, MD

ASSOCIATE FACULTY

Kim McBride, MD Christopher Walker, PhD

2019-2020 FELLOWS

Nicolas Abreu, MD (Gene Therapy Fellow) Renatta Knox, MD, PhD (Neuromuscular Fellow)

SUPPORT STAFF

Kathleen Church, Project Manager Tabatha Simmons, PhD, Project Manager/Director, Gene Therapy Clinical Research Unit

The Center for Gene Therapy again had a highly productive and collaborative year, facilitated by the NIH/NIAMS P50-funded Center of Research Translation (CORT) in Muscular Dystrophy Therapeutic Development, which focuses on rapidly moving innovative therapies toward the clinic.

This year saw the widespread adoption by the neuromuscular community of the first adeno-associated viral (AAV) treatment for spinal muscular atrophy (SMA) — onasemnogene abeparvovec, which was developed at Nationwide Children’s — as well as the first publication of highly promising data from the first-in-human trial of AAV-delivered microdystrophin in patients with Duchenne muscular dystrophy. In addition, the first clinical trial of viral-mediated exon skipping was initiated with Nationwide Children’s as the sole site, using an AAV-delivered U7 small nuclear RNA (U7snRNA) in patients with exon duplications, with a goal of expressing full-length dystrophin. Other gene therapy trials continued, including for two forms of limb girdle muscular dystrophy, for mucopolysaccharidosis types 3A and 3B, and for CLN3- and CLN6-related Batten disease. The operationalization of new trials was facilitated by the establishment of the Gene Therapy Clinical Research Unit, made available to all investigators.

Two additional faculty joined the center. Dr. Stephen Kaler relocated from the NICHD/NIH, with a longstanding interest in disorders of inherited neurometabolic, motor neuron and copper transport diseases, and ongoing translational programs that address Menkes disease and choroid plexus–targeted gene therapy for alpha-mannosidosis, among others. Dr. Allison Bradbury joined from the University of Pennsylvania, to further develop her translational programs in the leukodystrophies, including Krabbe disease.

Other highlights included development of a novel approach to visualizing the overexpression of DUX4, providing a novel tool for the study of the complex molecular mechanism responsible for facioscapulohumeral muscular dystrophy; a large animal study demonstrating the feasibility of systemic delivery of the GALGT2 gene as a surrogate gene therapy for DMD; and the validation of a novel reachable workspace as a measure of motor function in SMA.

Neurology: See page 104 for related information about the Section of Neurology at Nationwide Children’s.

GRANTS AWARDED TO CENTER FOR GENE THERAPY AND NEUROLOGY CLINICAL AND RESEARCH FACULTY JULY 1, 2019 – JUNE 30, 2020

$17,070,837

SELECTED PUBLICATIONS

Alfano LN, Miller NF, Iammarino MA, Moore Clingenpeel M, Lowes SL, Dugan ME, Kissel JT, Al Zaidy S, Tsao CY, Lowes LP. ACTIVE (Ability Captured Through Interactive Video Evaluation) workspace volume video game to quantify meaningful change in spinal muscular atrophy. Developmental Medicine & Child Neurology. 2020 Mar;62(3):303-309.

Amini Chermahini G, Rashnonejad A, Harper SQ. RNAscope in situ hybridization-based method for detecting DUX4 RNA expression in vitro. RNA. 2019 Sep;25(9):1211-1217.

Koboldt DC, Waldrop MA, Wilson RK, Flanigan KM. The Genotypic and Phenotypic Spectrum of BICD2 Variants in Spinal Muscular Atrophy. Annals of Neurology. 2020 Apr;87(4):487-496.

Lowes LP, Alfano LN, Arnold WD, Shell R, Prior TW, McColly M, Lehman KJ, Church K, Sproule DM, Nagendran S, Menier M, Feltner DE, Wells C, Kissel JT, Al-Zaidy S, Mendell JR. Impact of Age and Motor Function in a Phase 1/2A Study of Infants With SMA Type 1 Receiving Single-Dose Gene Replacement Therapy. Pediatric Neurology. 2019 Sep;98:39-45.

Mendell JR, Sahenk Z, Lehman K, Nease C, Lowes LP, Miller NF, Iammarino MA, Alfano LN, Nicholl A, Al-Zaidy S, Lewis S, Church K, Shell R, Cripe LH, Potter RA, Griffin DA, Pozsgai E, Dugar A, Hogan M, Rodino-Klapac LR. Assessment of Systemic Delivery of rAAVrh74.MHCK7.micro-dystrophin in Children With Duchenne Muscular Dystrophy: A nonrandomized Controlled Trial. JAMA Neurology. 2020 Jun 15:e201484.

Zygmunt DA, Xu R, Jia Y, Ashbrook A, Menke C, Shao G, Yoon JH, Hamilton S, Pisharath H, Bolon B, Martin PT. rAAVrh74.MCK. GALGT2 Demonstrates Safety and Widespread Muscle Glycosylation after Intravenous Delivery in C57BL/6J Mice. Molecular Therapy – Methods & Clinical Development. 2019 Oct 21;15:305-319.

Research Institute Reports

CENTER FOR INJURY RESEARCH AND POLICY

The Center for Injury Research and Policy, located in the Abigail Wexner Research Institute at Nationwide Children’s Hospital, works globally to reduce injury-related pediatric death and disability. Established in 1999, the center serves as a pioneer by translating cutting-edge injury research into education, advocacy and advances in clinical care. From design changes in consumer products to new public policy, the Center for Injury Research and Policy’s influence is leading the way to a safer world.

FACULTY

Gary A. Smith, MD, DrPH

Director Julie C. Leonard, MD, MPH Lara B. McKenzie, PhD, MA Henry Xiang, MD, MPH, PhD Jinzghen (Ginger) Yang, PhD, MPH Motao Zhu, MD, MS, PhD

POSTDOCTORAL FELLOWS

Marco Benedetti, PhD Lindsay Sullivan, PhD

The Center for Injury Research and Policy works from local to global levels to reduce death and disability due to injuries through research, education, advocacy and advances in clinical care. The center aims to improve the scientific understanding of the epidemiology, prevention, acute treatment, rehabilitation and biomechanics of injuries. It provides leadership in the development, implementation and scientific evaluation of public policy regarding control of injuries. The center has been awarded designation as an Injury Control Research Center (ICRC) by the Centers for Disease Control and Prevention since 2008. This designation was recently renewed through 2024. CIRP is one of only 9 centers nationally with this designation, and it is the only ICRC focused on pediatric injury research and prevention. The multidisciplinary Center for Pediatric Trauma Research at Nationwide Children’s, led by Henry Xiang, MD, MPH, PhD, conducts evidence-based trauma care and policy research to achieve the best outcomes for pediatric trauma patients. Focusing on pre-hospital emergency medical services, acute treatment and rehabilitation care, researchers associated with the Center for Pediatric Trauma Research help promote the Center for Injury Research and Policy’s mission. The Make Safe Happen® app helps parents and caregivers overcome a perceived “overwhelming amount of advice” to make their homes safer for children. Developed by a team led by Lara McKenzie, PhD, MA, it addresses the difficulties parents and caregivers face when trying to keep their homes safe for their children. It provides parents and caregivers with room-by-room safety checklists, and links to purchase recommended safety products. Recognizing that not all homes are the same, the app offers different solutions for different situations. Users can set reminders for activities, such as monthly smoke alarm testing or annual replacement of smoke alarm batteries. In 2016, a Home Fire Drill feature was added, so families can choose a safe meeting place and practice getting out of the home in less than two minutes. The Nationwide Make Safe Happen campaign for Home Fire Drill Day was the winner of the 2017 Halo Award in the category of Best Message-Focused Campaign. The free app is available for iOS and Android systems and has been downloaded more than 67,000 times since early 2015.

GRANTS AWARDED JULY 1, 2019 – JUNE 30, 2020

$4,972,023

SELECTED PUBLICATIONS

Coxe K, Sullivan L, Newton A, Yang JZ. Barriers to the implementation of State Concussion Laws within high schools. Journal of Adolescent Health. 2020 Feb;66(2):233-239.

Li A, Shen S, Nwosu A, Ratnapradipa K, Cooper J, Zhu M. Investigating traffic fatality trends and restraint use among rear-seat passengers in the United States, 2000-2016. Journal of Safety Research. 2020 Jun;73:9-16.

Merten JW, Roberts KJ, King JL, McKenzie LB. Pinterest Homemade Sunscreens: A Recipe for Sunburn. Health Communication. 2020 Aug;35(9):1123-1128.

Nattino G, Lu B, Shi J, Lemeshow S, Xiang H. Triplet Matching for Estimating Causal Effects With Three Treatment Arms: A Comparative Study of Mortality by Trauma Center Level. Journal of the American Statistical Association. 2020 Apr 3. [Epub ahead of print]

Smith GA, Chounthirath T, Splaingard M. Do Sleeping Children Respond Better to a Smoke Alarm That Uses Their Mother’s Voice? Academic Pediatrics. 2020 Apr;20(3):319-326.

Research Institute Reports

CENTER FOR INNOVATION IN PEDIATRIC PRACTICE

The mission of the Center for Innovation in Pediatric Practice in the Abigail Wexner Research Institute at Nationwide Children’s Hospital is to advance child health and well-being through research in and across clinical care, health services, health policy and community initiatives. We aspire to lead the nation in groundbreaking research that produces reduced disparities, vibrant communities, flourishing families and equitable and best outcomes for all children. Investigators at the center develop and test new health service delivery and payment systems in partnership with pediatricians, payers and Nationwide Children’s to improve quality and equity of care — especially for those patients most at risk.

FACULTY

Deena J. Chisolm, PhD

Director Susan E. Creary, MD, MSc Jennifer L. Dotson, MD, MPH Laura C. Hart, MD Kelly J. Kelleher, MD, MPH Alex R. Kemper, MD Amrik S. Khalsa, MD Sarah H. O’Brien, MD, MSc Jordee M. Wells, MD, MPH

CENTER FOR SURGICAL OUTCOMES RESEARCH

Jennifer N. Cooper, PhD Katherine J. Deans, MD, MHSc, Co-Director Daryl J. McLeod, MD Peter C. Minneci, MD, MHSc, Co-Director Prasanth Pattisapu, MD, MPH

CENTER FOR SUICIDE PREVENTION AND RESEARCH

Jeffrey A. Bridge, PhD, Director Arielle H. Sheftall, PhD Ohio Department of Medicaid, Dr. Deena Chisolm was awarded a $14.9 million Integrated Care for Kids (InCK) cooperative agreement from CMS to study innovative approaches to reducing out of home placement in rural, Medicaid-enrolled youth. Dr. Jordee Wells was awarded an NICHD diversity supplement to study racial disparities in pediatric head trauma follow-up care. Dr. Sarah O’Brien was named co-investigator on a new R21 awarded to Texas Children’s Hospital, studying iron deficiency anemia in African American girls. Notable publications explored novel approaches to adherence measurement for sickle cell disease, community development as an intervention for health and the health system’s role in advancing population health. Center for Surgical Outcomes Research faculty published results from their groundbreaking research on non-operative treatment of uncomplicated appendicitis along with research on disparities in pediatric tonsillectomy and opioid prescribing. The center welcomed Dr. Prasanth Pattisapu, ENT, as a new investigator. Center for Suicide Prevention and Research investigators explored early correlates of pediatric suicidality, trends in youth suicidal behavior and intensive crisis intervention. The center moved to its new space in the Big Lots Behavioral Health Pavilion, supporting expanded integration of research, treatment and prevention. Faculty member achievements include: Dr. Katherine Deans appointed as the Chief Clinical Science Officer in the Abigail Wexner Research Institute and Dr. Chisolm named as Nationwide Foundation Endowed Chair in Health Equity Research and appointed to the state’s Minority Health Task Force for COVID-19, Dr. Jeffrey Bridge named as Nationwide Foundation Endowed Chair in Innovation in Behavioral Health Research and Dr. Arielle Sheftall received a Young Investigator Award from the American Foundation for Suicide Prevention.

GRANTS AWARDED JULY 1, 2019 – JUNE 30, 2020

$2,955,692

SELECTED PUBLICATIONS

Chisolm DJ, Jones C, Root ED, Dolce M, Kelleher KJ. A Community Development Program and Reduction in High-Cost Health Care Use. Pediatrics. 2020 Aug;146(2):e20194053. Creary S, Chisolm DJ, Stanek J, Neville K, Garg U, Hankins JS, O’Brien SH. Measuring hydroxyurea adherence by pharmacy and laboratory data compared with video observation in children with sickle cell disease. Pediatric Blood & Cancer. 2020 Aug;67(8):e28250. Kemper AR, Kelleher KJ, Allen S, Sander C, Brilli RJ. Improving the Health of All Children in Our Community: The Nationwide Children’s Hospital and Franklin County, Ohio, Pediatric Vital Signs Project. The Journal of Pediatrics. 2020 Jul;222:227-230. [Epub May 13 2020] Minneci PC, Hade EM, Lawrence AE, Sebastião YV, Saito JM, Mak GZ, Fox C, Hirschl RB, Gadepalli S, Helmrath MA, Kohler JE, Leys CM, Sato TT, Lal DR, Landman MP, Kabre R, Fallat ME, Cooper JN, Deans KJ; Midwest Pediatric Surgery Consortium. Association of Nonoperative Management Using Antibiotic Therapy vs Laparoscopic Appendectomy With Treatment Success and Disability Days in Children With Uncomplicated Appendicitis. JAMA. 2020 Jul 27;324(6):581-593. Sheftall, A. H., Bergdoll, E. E., James, M., Bauer, C., Spector, E., Vakil, F., Armstrong, E., Allen, J., & Bridge, J. A. Emotion Regulation in Elementary School-Aged Children with a Maternal History of Suicidal Behavior: A Pilot Study. Child Psychiatry and Human Development. 2020 Jun 1. [Epub ahead of print]

Research Institute Reports

CENTER FOR MICROBIAL PATHOGENESIS

The emphasis of the Center for Microbial Pathogenesis in the Abigail Wexner Research Institute at Nationwide Children’s Hospital is to develop a greater understanding of the molecular mechanisms by which microorganisms cause disease, as well as how the host responds to these disease states. Faculty within the center identify virulence mechanisms and define host response patterns, with the overall objective of elucidating a detailed description of the structure, function and control of biological systems in health and disease via use of molecular and cellular, as well as genomic, proteomic, transcriptomic and metabolomic approaches. This information is then translated into novel diagnostics, improved therapeutics and more broadly effective vaccines.

FACULTY

Lauren O. Bakaletz, PhD

Director Michael T. Bailey, PhD Jennifer L. Edwards, PhD Steven D. Goodman, PhD John S. Gunn, PhD Sheryl S. Justice, PhD Samantha J. King, PhD Benjamin T. Kopp, MD Ross M. Maltz, MD Kevin M. Mason, PhD Christopher P. Montgomery, MD Santiago Partida-Sanchez, PhD Chack-Yung Yu, PhD

Each faculty member within the center highlighted a noteworthy accomplishment for the 2019-2020 academic year. Michael Bailey, PhD, and his team discovered that the production of reactive oxygen intermediates by intestinal epithelial cells, a primary mechanism by which the host response to stressful stimuli, leads to changes in the gut microbiome. Lauren Bakaletz, PhD, and Steven Goodman, PhD, cite both their recent publication in Proceedings of the National Academy of Sciences and the successful co-founding and launch of Clarametyx Biosciences Inc. to move forward promising technology that disrupts diverse pathogenic biofilms. The laboratory of Jennifer Edwards, PhD, identified and patented two nontraditional antibiotics that can be used to prevent and cure female cervical infection by “untreatable” Neisseria gonorrhoeae. John Gunn, PhD, was awarded two new National Institutes of Health grants important to ongoing research into the mechanisms of gallstone biofilm-related chronic carriage of Salmonella. Sheryl Justice, PhD, demonstrated that bacterial mutants enhance formation of intracellular bacterial communities, providing more insight into the nutritional requirements for intracellular growth. Samantha King, PhD, was awarded a new R21 grant by the National Institute of Allergy and Infectious Diseases to study the serine-rich repeat protein adhesin of the infective endocarditis pathogen Streptococcus oralis. Ben Kopp, MD, was awarded his first R01 National Institutes of Health/National Heart Lung and Blood Institute grant titled, “The role of CFTR during macrophage-mediated killing of bacteria.” The laboratory of Ross Maltz, MD, launched a longitudinal clinical trial in pediatric Crohn’s disease and developed two murine models for use in his research. Kevin Mason, PhD, developed a sequential model of otitis media to investigate microevolution through genetic mutations that modulate disease severity. The laboratory of Christopher Montgomery, MD, demonstrated that genetically determined immunodominance inhibits “natural” protective immunity against Staphylococcus aureus infection in mice, but vaccination overcomes this restriction. Santiago Partida-Sanchez, PhD, was awarded a grant by the Cystic Fibrosis Foundation and published six research articles. Chack-Yung Yu, PhD, obtained evidence for a role complement C4 and C3 phenotypic and genotypic diversity as risk factors for cardiovascular diseases. Infectious Diseases: See page 88 for information about the Division of Infectious Diseases at Nationwide Children’s.

GRANTS AWARDED JULY 1, 2019 – JUNE 30, 2020

$4,028,402

SELECTED PUBLICATIONS

Devaraj A, Buzzo JR, Marshburn-Warren L, Novotny LA, Bakaletz LO, Goodman SD. The Extracellular DNA Lattice of Bacterial Biofilms is Structurally Related to Holliday Junction Recombination Intermediates. Proceedings of the National Academy of Sciences of the United States of America. Dec 2019;116(50):25068-25077.

González JF, Kurtz J, Bauer DL, Hitt R, Fitch J, Wetzel A, La Perle K, White P, McLachlan J, Gunn JS. Establishment of Chronic Typhoid Infection in a Mouse Carriage Model Involves a Type 2 Immune Shift and T and B Cell Recruitment to the Gallbladder. mBio. Oct 2019;10(5):e02262-19.

Harrison A, Hardison RL, Fullen AR, Wallace RM, Gordon DM, White P, Jennings RN, Justice SS, Mason KM. Continuous Microevolution Accelerates Disease Progression During Sequential Episodes of Infection. Cell Reports. Mar 2020;30(9):2978-2988.

Poole J, Day CJ, Haselhorst T, Jen FE-C, Torres VJ, Edwards JL, Jennings MP. Repurposed Drugs that Block the Gonococcal-Complement Receptor 3 Interaction Can Prevent and Cure Gonococcal Infection of Primary Human Cervical Epithelial Cells. mBio. Mar 2020;11(2):e03046-19.

Si Y, Zhao F, Beesetty P, Weiskopf D, Li Z, Tian Q, Alegre ML, Sette A, Chong AS, Montgomery CP. Inhibition of Protective Immunity Against Staphylococcus aureus Infection by MHC-Restricted Immunodominance is Overcome by Vaccination. Science Advances. Apr 2020;6(14):eaaw7713.

Research Institute Reports

CENTER FOR PERINATAL RESEARCH

The Center for Perinatal Research in the Abigail Wexner Research Institute at Nationwide Children’s Hospital has a unique, integrative approach to prematurity research that extends from before birth to long after. In close collaboration with the Section of Neonatology, the mission of faculty in the Center for Perinatal Research is to conduct innovative basic, translational and clinical research focused on prevention of preterm birth and improvement of prematurity-related outcomes.

FACULTY

Lynette K. Rogers, PhD

Interim Director Carl H. Backes, MD Kristen Benninger, MD Gail E. Besner, MD Rodney Britt, PhD Bernadette Chen, MD Sudarshan R. Jadcherla, MD Mark A. Klebanoff, MD, MPH Yusen Liu, PhD Nathalie Maitre, MD, PhD Mary Lauren Neel, MD Leif D. Nelin, MD Leeann R. Pavlek, MD, MPH Susan Reynolds, PhD Pablo Sanchez, MD Jonathan L. Slaughter, MD, MPH Jennifer K. Trittmann, MD, MPH Complications from preterm birth are the leading cause of infant mortality and morbidity. The investigators in the Center for Perinatal Research focus on prevention of prematurity and understanding and treating the complications that occur in as a result of preterm birth. Our diverse team encompasses expertise in both basic science and clinical investigations. The basic science group explores the mechanisms involved in development of chronic lung disease such as bronchopulmonary dysplasia (Rogers), pulmonary hypertension (Nelin, Chen, Trittmann) and asthma (Britt), infection and inflammation (Liu), use of stem cell therapy in diagnosing and treating cystic fibrosis (Reynolds) and GI disorders such as necrotizing enterocolitis (Besner). Our diverse clinical research delves into prematurity prevention and maternal health (Klebanoff), infant feeding disorders (Jadcherla), infectious diseases (Sanchez), comparative effectiveness in pharmacoepidemiology (Slaughter), cardiopulmonary deficiencies (Backes, Pavlek) and development of novel treatments and approaches for improving outcomes in infants with neurological disorders or injuries (Maitre, Neel, Benninger). The center received more than $600,000 in new prime NIH funding this year. Collectively, the Center for Perinatal Research brought in $4.1 million in NIH funding and $1.2 million in foundation and industry grants for the purpose of research. The center also is home to one of the sites of the Neonatal Research Network, a consortium of 17 institutions from across the United States funded by the NIH to conduct randomized, controlled trials of promising therapies and observational studies to advance care of highest risk newborns. In addition, our accomplished investigators have filed multiple patents for devices to improve infant outcomes. Neonatology: See page 94 for information about Neonatology, home to one of the largest networks of clinical neonatal care in the United States.

GRANTS AWARDED TO NEONATOLOGY CLINICAL AND RESEARCH FACULTY JULY 1, 2019 – JUNE 30, 2020

$5,562,391

SELECTED PUBLICATIONS

Benninger KL, Inder TE, Goodman AM, Cotten CM, Nordli DR, Shah TA, Slaughter JL, Maitre NL. Perspectives from the Society for Pediatric Research. Neonatal encephalopathy clinical trials: developing the future. Pediatric Research. 2020 Mar 27. [Epub ahead of print] Galley JD, Besner GE. The Therapeutic Potential of Breast Milk-Derived Extracellular Vesicles. Nutrients. 2020 Mar 11;12(3):745. Jadcherla SR, Hasenstab KA, Wei L, Osborn EK, Viswanathan S, Gulati IK, Slaughter JL, Di Lorenzo C. Role of feeding strategy bundle with acid-suppressive therapy in infants with esophageal acid reflux exposure: a randomized controlled trial. Pediatric Research. 2020 May 7. [Epub ahead of print] Klebanoff MA, Wilkins DG, Keim SA. Marijuana Use during Pregnancy and Preterm Birth: A Prospective Cohort Study. American Journal of Perinatology. 2020 Apr 1. [Epub ahead of print] Pavlek LR, Vudatala S, Bartlett CW, Buhimschi IA, Buhimschi CS, Rogers LK. MiR-29b is associated with perinatal inflammation in extremely preterm infants. Pediatric Research. 2020 May 9. [Epub ahead of print]

Research Institute Reports

CENTER FOR REGENERATIVE MEDICINE

The Center for Regenerative Medicine in the Abigail Wexner Research Institute at Nationwide Children’s Hospital applies the principles of engineering, computer modeling and life sciences to develop biological substitutes to restore or improve tissue function. Regenerative medicine is the process of creating living, functional tissues to repair or replace tissue or organ functions, lost primarily due to congenital defects or disease. The center currently focuses on producing blood vessels, valvular patches and heart valves, offering a positive impact on children with congenital heart disease. Other areas of regenerative medicine research in progress include intestinal and tracheal replacement.

FACULTY

Christopher K. Breuer, MD

Director

Tendy Chiang, MD Oluyinka O. Olutoye, MD, PhD Toshiharu Shinoka, MD, PhD Mitchel R Stacy, PhD

Medical advances have made it possible to save more patients from life-threatening injuries, diseases and congenital conditions. However, after the onset of these conditions, the damage is occasionally lifelong. Often, symptoms can be treated with success, but the underlying tissue or organ damage remains unhealed and can cause further complications over time. To develop new clinical applications that address the unmet needs of these patients, the AWRI at Nationwide Children’s established the Center for Regenerative Medicine in 2017. Center for Regenerative Medicine clinicians and researchers, led by Christopher Breuer, MD, are creating biological vessels, intestines and tracheas; identifying tissue progenitor cells, and developing ways to enhance tissue repair and growth. To further diversify the center’s research strengths, we are actively recruiting principal investigators. Our vision is to pioneer new approaches in tissue regeneration and to develop next-generation reparative solutions. Further, we believe it is our responsibility to learn from every patient so our care for the next child will be improved. This has been an exciting year for the center. Not only have we made significant progress on our NIH-funded research, we have fostered collaborations with outside sponsors to help develop the next generation of tissueengineered blood vessels. We have also brought on board Oluyinka Olutoye, MD, the new Surgeon-inChief at Nationwide Children’s, whose research focus is regenerating intestinal tissue to assist with infants battling necrotizing enterocolitis. Excitingly, we have also begun the second phase of our human TissueEngineered Vascular Graft (TEVG) clinical trial for patients undergoing a Fontan repair. This NIH funded project’s goal is to further our work on using the body’s innate repair mechanisms to assist patients with congenital heart defects. Ultimately, this comprehensive approach means that the Center for Regenerative Medicine has the ability to turn promising laboratory discoveries into proven treatments and make them available to patients.

GRANTS AWARDED JULY 1, 2019 – JUNE 30, 2020

$2,145,809

SELECTED PUBLICATIONS

Chou TH, Stacy MR. Clinical Applications for Radiotracer Imaging of Lower Extremity Peripheral Arterial Disease and Critical Limb Ischemia. Molecular Imaging and Biology. 2020;22(2):245-255.

Fukunishi T, Ong CS, Yesantharao P, Breuer CK, et al. Different degradation rates of nanofiber vascular grafts in small and large animal models. Journal of Tissue Engineering and Regenerative Medicine. 2020;14(2):203-214.

Liu L, Rodman C, Worobetz NE, Johnson J, Elmaraghy C, Chiang T. Topical biomaterials to prevent post-tonsillectomy hemorrhage. Journal of Otolaryngology - Head & Neck Surgery. 2019 Sep;48(1):45.

Molina TL, Stoll B, Mohammad M, Olutoye O, et al. New generation lipid emulsions increase brain DHA and improve body composition, but not short-term neurodevelopment in parenterally fed preterm piglets. Brain, Behavior, and Immunity. 2020;85:46-56.

Szafron JM, Ramachandra AB, Breuer CK, Marsden AL, Humphrey JD. Optimization of Tissue-Engineered Vascular Graft Design Using Computational Modeling. Tissue Engineering Part C: Methods. 2019;25(10):561-570.

Research Institute Reports

CENTER FOR VACCINES AND IMMUNITY

The Center for Vaccines and Immunity in the Abigail Wexner Research Institute at Nationwide Children’s Hospital has a single purpose: to improve the health of children through fundamental and applied research leading to a new generation of safe, protective vaccines against infection, cancer and allergy.

FACULTY

Chris Walker, PhD

Director Zongdi Feng, PhD Jonathan Honegger, MD Amit Kapoor, PhD Asuncion Mejias, MD, PhD, MSCS Mark Peeples, PhD Octavio Ramilo, MD Masako Shimamura, MD Zhaohui Xu, PhD

Nine investigators in the Center for Vaccines and Immunity study viral diseases of childhood. Respiratory syncytial virus (RSV) is the leading cause of hospitalization for young children. Over the past year, center investigators made notable advances in RSV vaccine design and our understanding of factors contributing to the severity of airway disease. A key objective of RSV research is to identify predictive markers of mild and severe disease to facilitate development of vaccines and therapeutics. A study from Asuncion Mejias, MD, Octavio Ramilo, MD, and Mark Peeples, PhD, in the highly influential journal, Science Translational Medicine, described an immune profile that distinguishes mild from severe RSV disease. Children with mild disease harbored more virus and produced more interferon, a key component of the early protective immune response. They also had lower levels of inflammation than children with severe disease. These findings provide valuable insights into the host immune response to RSV. Center researchers also study hepatitis virus infections. The hepatitis C virus (HCV) causes a persistent lifelong infection. It is of particular concern as it is transmitted to children from mothers at birth and by injection drug use during adolescence. Jonathan Honegger, MD, published a study in the prestigious Journal of Clinical Investigation that linked recovery of a key mediator of antiviral immunity, the T helper cell, to unexpected control of chronic HCV infection in women after childbirth. Understanding how immune reconstitution occurs in the unique setting of pregnancy is expected to have a much broader impact on strategies to treat chronic infections and develop effective vaccines. Finally, Amit Kapoor, PhD, provided important new insight into how HCV-like viruses evade immunity to establish a persistent infection using a novel rodent infection model that he discovered. This model holds great promise to define mechanisms of protective immunity and to assess new vaccine concepts to protect against a virus that takes a great toll on public health in the United States and globally. Infectious Diseases: See page 88 for information about the Division of Infectious Diseases at Nationwide Children’s.

GRANTS AWARDED JULY 1, 2019 – JUNE 30, 2020

$5,044,969

SELECTED PUBLICATIONS

Coss SL, Torres-Cornejo A, Prasad MR, Moore-Clingenpeel M, Grakoui A, Lauer GM, Walker CM, Honegger JR. CD4+ T Cell Restoration and Control of Hepatitis C Virus Replication after Childbirth. The Journal of Clinical Investigation. 2020 Feb 3;130(2):748753.

Hartlage AS, Walker CM, Kapoor A. Priming of Antiviral CD8 T Cells without Effector Function by a Persistently Replicating Hepatitis C-like Virus. The Journal of Virology. 2020 May 4;94(10):e00035-20.

Heinonen S, Velazquez VM, Ye F, Mertz S, Acero-Bedoya S, Smith B, Bunsow E, GarciaMauriño C, Oliva S, Cohen DM, Moore-Clingenpeel M, Peeples ME, Ramilo O, Mejias A. Immune Profiles Provide Insights into Respiratory Syncytial Virus Disease Severity in Young Children. Science Translational Medicine. 2020 Apr 22;12(540):eaaw0268.

Lu M, Zhang Z, Xue M, Zhao BS, Harder O, Li A, Liang X, Gao TZ, Xu Y, Zhou J, Feng Z, Niewiesk S, Peeples ME, He C, Li J. N6-methyladenosine Modification Enables Viral RNA to Escape Recognition by RNA Sensor RIG-I. Nature Microbiology. 2020 Apr;5(4):584-598.

Ramilo O, Rodriguez-Fernandez R, Peeples ME, Mejias A. Advanced Live Attenuated Vaccines for the Prevention of Respiratory Syncytial Virus Infections in Young Children. The Journal of Infectious Diseases. 2020 Jun 16;222(1):4-6.