Umbilical cord blood transplantation to treat Pelizaeus-Merzbacher Disease in 2 young boys.

Abstract

Pelizaeus-Merzbacher Disease (PMD) is a rare X-linked recessive leukodystrophy caused by mutations in the proteolipid protein 1 gene on the Xq22 chromosome. PMD is a dysmyelinating disorder characterized by variable clinical presentation and course. Symptoms range from mild motor deficits to progressive spasticity and neurologic decline resulting in death at an early age. There is no definitive curative treatment. This report presents the clinical course of 2 young boys with PMD who are the first known patients to receive umbilical cord blood transplantation as a therapeutic intervention to stabilize disease progression. Pretransplantation evaluation revealed that both patients had significant motor deficits as well as delayed cognitive function as compared with age-matched peers. Brain imaging revealed varying degrees of hypomyelination. Both patients received myeloablative chemotherapy followed by an unrelated donor umbilical cord blood infusion, which they tolerated well with no major transplantation-related complications. At 7-years and 1-year posttransplantation, respectively, both boys are making slow neurocognitive improvements and show no evidence of functional decline. Imaging results show stable or improving myelination. Although the results of unrelated donor umbilical cord blood transplantation in these 2 boys with PMD are encouraging, longer-term follow-up will be necessary to assess the effect of this treatment on the variable natural disease course.

Department

Description

Provenance

Citation

Published Version (Please cite this version)

10.1542/peds.2013-3604

Publication Info

Wishnew, Jessica, Kristin Page, Susan Wood, Leo Galvin, James Provenzale, Maria Escolar, Kathryn Gustafson, Joanne Kurtzberg, et al. (2014). Umbilical cord blood transplantation to treat Pelizaeus-Merzbacher Disease in 2 young boys. Pediatrics, 134(5). pp. e1451–e1457. 10.1542/peds.2013-3604 Retrieved from https://hdl.handle.net/10161/24711.

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Scholars@Duke

Provenzale

James Michael Provenzale

Professor of Radiology

I have the following major research areas:
I. Diffusion tensor imaging (an MR technique that measures rate and direction of microscopic water motion) to examine white matter pathways in the brain. This technique is used by many investigators in an attempt to understand white matter microstructure. My recent work has centered on the histological correlation of DTI metrics. In addition, because DTI metrics can vary substantially within a single scanner at multiple time points as well as between scanners, my work is focused on understanding causes of such variability and designing methods to decrease it. 
Since 1998, I have mentored third-year students at Duke University School of Medicine (typically one medical student per year) in both DTI research and perfusion imaging research. Although the research techniques are highly advanced, our implementation of various "user-friendly" software programs allows students with little or no prior experience to analyze data in a productive manner. Our research is also well-suited to individuals with advanced computer skills or an interest in biomedical or electrical engineering. Students work closely with research personnel on a daily basis. They also meet with collaborators from various basic science and clinical departments and me in a laboratory meeting once a week. The focus of these meetings is to plan experiments, refine research methods, discuss experimental results and prepare manuscripts. Students serve as first authors or co-authors on manuscripts based on their specific research project. The results of a number of such projects have been published.

II. Applications of nanotechnology to treatment of cancer (both CNS and non-CNS) and brain disorders. My research involves design and implementation of nanoparticles and fluorescent molecules for cancer diagnosis and therapy. Although I am trained as a neurologist and neuroradiologist, most of my nanotechnology-based research is oriented towards non-CNS tumors such as breast cancer and sarcomas. In the past few years, my Emory and Georgia Tech colleagues and I have conducted research using animals with naturally-occurring tumors at the University of Georgia College of Veterinary Medicine. This work has focused on the use of a handheld device to detect fluorophores that are administered intravenously prior to surgery. We are presently validating the use of this combination of imaging device and contrast agent to guide surgical resection of tumors. I am also interested in development of nanotechnology-based non-invasive and minimally invasive devices that can continuously monitor tumor physiological characteristics and response to therapy. This work is done in conjunction with a number of colleagues in Biomedical Engineering at both Duke and Emory and supported by a number of NIH grants. Finally, I have a strong interest in use of nanotechnology for tissue engineering and regenerative medicine. 

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.

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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