Effect of Autologous Cord Blood Infusion on Motor Function and Brain Connectivity in Young Children with Cerebral Palsy: A Randomized, Placebo-Controlled Trial.

Abstract

Cerebral palsy (CP) is a condition affecting young children that causes lifelong disabilities. Umbilical cord blood cells improve motor function in experimental systems via paracrine signaling. After demonstrating safety, we conducted a phase II trial of autologous cord blood (ACB) infusion in children with CP to test whether ACB could improve function (ClinicalTrials.gov, NCT01147653; IND 14360). In this double-blind, placebo-controlled, crossover study of a single intravenous infusion of 1-5 × 107 total nucleated cells per kilogram of ACB, children ages 1 to 6 years with CP were randomly assigned to receive ACB or placebo at baseline, followed by the alternate infusion 1 year later. Motor function and magnetic resonance imaging brain connectivity studies were performed at baseline, 1, and 2 years post-treatment. The primary endpoint was change in motor function 1 year after baseline infusion. Additional analyses were performed at 2 years. Sixty-three children (median age 2.1 years) were randomized to treatment (n = 32) or placebo (n = 31) at baseline. Although there was no difference in mean change in Gross Motor Function Measure-66 (GMFM-66) scores at 1 year between placebo and treated groups, a dosing effect was identified. In an analysis 1 year post-ACB treatment, those who received doses ≥2 × 107 /kg demonstrated significantly greater increases in GMFM-66 scores above those predicted by age and severity, as well as in Peabody Developmental Motor Scales-2 Gross Motor Quotient scores and normalized brain connectivity. Results of this study suggest that appropriately dosed ACB infusion improves brain connectivity and gross motor function in young children with CP. Stem Cells Translational Medicine 2017;6:2071-2078.

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Description

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Citation

Published Version (Please cite this version)

10.1002/sctm.17-0102

Publication Info

Sun, Jessica M, Allen W Song, Laura E Case, Mohamad A Mikati, Kathryn E Gustafson, Ryan Simmons, Ricki Goldstein, Jodi Petry, et al. (2017). Effect of Autologous Cord Blood Infusion on Motor Function and Brain Connectivity in Young Children with Cerebral Palsy: A Randomized, Placebo-Controlled Trial. Stem cells translational medicine, 6(12). pp. 2071–2078. 10.1002/sctm.17-0102 Retrieved from https://hdl.handle.net/10161/24589.

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Scholars@Duke

Jessica Muller Sun

Associate Professor of Pediatrics
Song

Allen W Song

Professor in Radiology

The research in our lab is concerned with advancing structural and functional MRI methodologies (e.g. fast and high-resolution imaging techniques) for human brain imaging. We also aim to improve our understanding of functional brain signals, including spatiotemporal characterizations of the blood oxygenation level dependent contrast and alternative contrast mechanisms that are more directly linked to the neuronal activities. Additional effort is invested in applying and validating the developed methods to study human functional neuroanatomy.

Case

Laura Elizabeth Case

Associate Professor in Orthopaedic Surgery

Laura E Case, PT, DPT, MS, PhD, PCS, C/NDT is a board-certified clinical specialist in pediatric physical therapy. She has dedicated her career to teaching, research in childhood-onset neuromusculoskeletal disorders, and to the lifelong treatment of people with childhood-onset neurological and neuromuscular disorders such as cerebral palsy, traumatic brain injury, Duchenne muscular dystrophy, spinal muscular atrophy, Pompe disease, myelodysplasia, juvenile rheumatoid arthritis, and brachial plexus injury.

She has been involved in numerous clinical trials for the treatment of disorders including Pompe disease and other metabolic disorders, cerebral palsy, Duchenne muscular dystrophy, and spinal muscular atrophy. Dr. Case has participated in the development of international guidelines for the management of Duchenne muscular dystrophy, Pompe disease, and other glycogen storage diseases.

She teaches and consults internationally, has worked on a number of Center for Disease Control (CDC) task forces, has served on numerous committees and task forces in the pediatric section of APTA, served two terms as NC State Representative to the APTA Section on Pediatrics, and is a member of the North American Pompe Registry Board of Advisors.

Mikati

Mohamad Abdul Mikati

Wilburt C. Davison Distinguished Professor

Mohamad A.  Mikati M.D., is the Wilburt C. Davison Professor of Pediatrics, Professor of Neurobiology, and Chief of the Division of Pediatric Neurology. Dr. Mikati’s clinical research has centered on characterization and therapy of pediatric epilepsy and neurology syndromes, describing several new pediatric neurological entities with two carrying his name (POSSUM syndromes # 3708 and 4468), developing novel therapeutic strategies for epilepsy and related disorders particularly Alternating Hemiplegia of Childhood, and applying cutting edge genetic and Magnetic Resonance Imaging techniques to drug resistant pediatric epilepsy.  In the laboratory he has elucidated mechanisms of seizure related neuronal injury, particularly those related to the ceramide pathway, and demonstrated neuroprotective effects of several agents including erythropoietin. Most recently he has concentrated his laboratory research on the pathophysiology of ATP1A3 dysfunction in the brain as model for epilepsy and of Alternating Hemiplegia of Childhood. He has more than 290 peer reviewed publications, 400 abstracts 41 chapters one book and two booklets. He also has more than 10,497 citations in the literature with an h-index of 58 and an i-10index of 190. Dr. Mikati has written chapters on epilepsy and related disorders in the major textbooks of Pediatrics and Pediatric Neurology including Swaiman’s Pediatric Neurology and Nelson’s Pediatrics. Before joining Duke in 2008 he had completed his M.D. and Pediatric training at the American University of Beirut, his Neurology at the Massachusetts General Hospital, his Neurophysiology at Boston Children’s Hospital and had been on the Faculty at Harvard as Director of Research in the Epilepsy Program at Boston Children’s Hospital and then as Professor and Chairman, Department of Pediatrics, Founder and Director of the Adult and Pediatric Epilepsy Program at the American University of Beirut. Dr. Mikati has had several international leadership roles including being President of the Union of the Middle Eastern and Mediterranean Pediatric Societies, on the Standing Committee of the International Pediatric Association (IPA), Chair of the Strategic Advisory Group on Early Childhood Development of the IPA, Officer of the International Child Neurology Association, Consultant to UNICEF, WHO, and the American Board of Pediatrics. He was selected to organize and chair the American Epilepsy Society's Merritt-Putnam Symposium and was one of only two Pediatric Neurologists, initially chosen worldwide, on the WHO advisory committee for the International Classification of Disease. He has received several national and international honors including, among others, Merritt Putnam American Epilepsy Society Fellowship Award, Harvard Community Health Plan Peer recognition Award, Debs Research Award, Hamdan Award for contributions to Medicine, Hans Zellweger Award for contributions to Pediatric Neurology, Patient Choice Award and the Michael Frank Award for research and lifetime contributions to the field of Pediatric Neurology.

Gustafson

Kathryn E. Gustafson

Professor in Psychiatry and Behavioral Sciences

My scholarly interests and expertise are in pediatric neurodevelopmental outcomes assessment and research as well as child and parent coping with chronic childhood illness. I collaborated with Dr. Robert Thompson on a research program investigating the transactional biopsychosocial model of adaptation to pediatric conditions in children and families. Our research program was funded by the NIH and culminated in the publication of our book, Adaptation to Chronic Childhood Illness. In addition, because of my expertise in neurodevelopmental functioning, I collaborate with the Division of Neonatology and the Duke Neonatal-Perinatal Research Unit on neurodevelopmental outcomes research with high-risk infants, toddlers, and school-age children. I am a gold standard psychology consultant to the Neonatal Research Network (NRN) of the NIH/NICHD, train and certify psychologists around the country in infant and toddler developmental assessment, and serve as consultant for protocol development.  In addition, I collaborate with colleagues in Pediatric Ophthalmology to investigate preterm optic nerve anatomy assessed via optical coherence tomography imaging and the association with neurodevelopment. I am also involved in investigations of umbilical cord blood stem cell transplant for young children with hypoxic ischemic encephalopathy, cerebral palsy, and inborn errors of metabolism with colleagues in the Blood and Marrow Transplantation program.

Colleen A McLaughlin

Clinical Associate in the School of Nursing
Worley

Gordon Worley

Professor Emeritus of Pediatrics

Dr. Gordon Worley specializes in Neurodevelopmental Disabilities, a sub-specialty of Pediatrics focusing on  the management of the medical problems of children with physical disabilities. The principal diagnoses he treats are cerebral palsy, spina bifida, and Down syndrome. HIs research pertains to clinical problems of children with these conditions. Current research interests include genetic factors influencing outcomes of Extremely Low Birth Weight Infants using analyses of a large data set; comparison of outcomes of prenatal (in utero) surgery vs postnatal  for lesion closure in meningomyelocele using the National Spina Bifida Patient Registry; Down Syndrome Disintegrative Disorder; and associations of ADHD with high risk sexual behaviors using analyses of a large data set.

Troy

Jesse David Troy

Associate Professor of Biostatistics & Bioinformatics

I am the Associate Director of Graduate Studies for the Master of Biostatistics program. I am also an instructor in the Clinical Research Training Program. I work on research studies in cancer therapeutics and palliative care at the Duke Cancer Institute.

Kurtzberg

Joanne Kurtzberg

Jerome S. Harris Distinguished Professor of Pediatrics

Dr. Kurtzberg is an internationally renowned expert in pediatric hematology/oncology, pediatric blood and marrow transplantation, umbilical cord blood banking and transplantation, and novel applications of cord blood and birthing tissues in the emerging fields of cellular therapies and regenerative medicine.   Dr. Kurtzberg serves as the Director of the Marcus Center for Cellular Cures (MC3), Director of the Pediatric Transplant and Cellular Therapy Program, Director of the Carolinas Cord Blood Bank, and Co-Director of the Stem Cell Transplant Laboratory at Duke University.  The Carolinas Cord Blood Bank is an FDA licensed public cord blood bank distributing unrelated cord blood units for donors for hematopoietic stem cell transplantation (HSCT) through the CW Bill Young Cell Transplantation Program.  The Robertson GMP Cell Manufacturing Laboratory supports manufacturing of RETHYMIC (BLA, Enzyvant, 2021), allogeneic cord tissue derived and bone marrow derived mesenchymal stromal cells (MSCs), and DUOC, a microglial/macrophage cell derived from cord blood.

Dr. Kurtzberg’s research in MC3 focuses on translational studies from bench to bedside, seeking to develop transformative clinical therapies using cells, tissues, molecules, genes, and biomaterials to treat diseases and injuries that currently lack effective treatments. Recent areas of investigation in MC3 include clinical trials investigating the safety and efficacy of autologous and allogeneic cord blood in children with neonatal brain injury – hypoxic ischemic encephalopathy (HIE), cerebral palsy (CP), and autism. Clinical trials testing allogeneic cord blood are also being conducted in adults with acute ischemic stroke. Clinical trials optimizing manufacturing and testing the safety and efficacy of cord tissue MSCs in children with autism, CP and HIE and adults with COVID-lung disease are underway. DUOC, given intrathecally, is under study in children with leukodystrophies and adults with primary progressive multiple sclerosis.

In the past, Dr. Kurtzberg has developed novel chemotherapeutic drugs for acute leukemias, assays enumerating ALDH bright cells to predict cord blood unit potency, methods of cord blood expansion, potency assays for targeted cell and tissue based therapies. Dr. Kurtzberg currently holds several INDs for investigational clinical trials from the FDA.  She has also trained numerous medical students, residents, clinical and post-doctoral fellows over the course of her career.


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